Use of biomarkers and therapeutic agents with surgical devices

ABSTRACT

Biomarkers are collected and used to determine biological propensities of a patient, to determine the efficacy of medical devices, to select and administer therapeutic agents, to select medical devices, to make adjustments to medical devices, and/or to adjust surgical techniques. An apparatus includes a port to draw a biological fluid (e.g., a mist) from a surgical site. The apparatus includes a sensor having a cantilevered beam. The beam includes substances selected to attract certain biomarkers as the fluid is communicated across the beam. The same apparatus or another apparatus is used to administer a therapeutic agent based at least in part on collected biomarker data. The therapeutic agent delivery apparatus may include a device that is also used to create a wound at a surgical site. For instance, a harmonic surgical instrument may be used to both collect biomarkers and administer a therapeutic agent (e.g., gene therapy using sonoporation).

PRIORITY

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/288,375, entitled “Method of Developing Surgical DevicesUsing Biomarkers,” filed Dec. 21, 2009, the disclosure of which isincorporated by reference herein.

BACKGROUND

Tissue trauma resulting in a wound may be an unavoidable consequence ofaccidental or intentional injury (e.g., from surgery, etc.). The processof wound healing is thought by some to take place in four stages. Thefirst stage is hemostasis which may begin immediately after the cuttingoccurs. In hemostasis, clotting may occur by natural means of plateletdegranulation. Hemostasis may also be induced by artificial means toaffect protein denaturation. The second stage is inflammation. In thisstage, the immune system may provide a response to the threat ofpossible infection via signaling to defensive immune cells such asneutrophils and macrophages. The third stage is the proliferation stage.In this stage, fibroblasts may enter the wound area and produce largeamounts of collagen that result in scar formation. A prolongedhemostatic or inflammatory stage may result in additional scar formationthat delays both this third stage and the final stage of wound healing.The final stage of wound healing is remodeling. This may occur once ascar has formed and the breaking strength of the wound begins toincrease. In this stage, the temporary collagen may be replaced bypermanent tissue and the scar slowly fades. The duration of this finalstage may depend upon how much scar tissue was formed in the previousstage.

While a variety of methods for monitoring the progress of wound healinghave been made and used, it is believed that no one prior to theinventor(s) has made or used the technology as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

While the specification concludes with claims which particularly pointout and distinctly claim this technology, it is believed this technologywill be better understood from the following description of certainexamples taken in conjunction with the accompanying drawings, in whichlike reference numerals identify the same elements and in which:

FIG. 1 depicts a flow diagram of an exemplary method of processingbiomarkers;

FIG. 2 depicts a side view of an exemplary harmonic surgical instrumenthaving a biomarker collection feature;

FIG. 3 depicts a partial view of the end effector of the harmonicsurgical instrument of FIG. 2;

FIG. 4 depicts a schematic view of an exemplary biomarker collection andprocessing system;

FIG. 5 depicts a schematic view of biomarker processing components ofthe system of FIG. 4;

FIG. 6 depicts a partial perspective view of a biomarker sensor of thesystem of FIG. 4, during a biomarker collection phase;

FIG. 7 depicts a partial perspective view of the biomarker sensor ofFIG. 6, during a sensor cleansing phase;

FIG. 8 depicts a schematic view of an exemplary surgical instrumentsystem including biomarker sensor feedback, where the biomarker sensorfeedback is used to automatically control or adjust a surgicalinstrument;

FIG. 9 depicts a schematic view of another exemplary surgical instrumentsystem including biomarker sensor feedback, where the biomarker sensorfeedback is used to control an agent administration device;

FIG. 10 depicts a schematic view of another exemplary surgicalinstrument system including biomarker sensor feedback, where biomarkersensor feedback is provided to the user through a user feedback featureof a surgical instrument;

FIG. 11 depicts a schematic view of another exemplary surgicalinstrument system including biomarker sensor feedback, where biomarkersensor feedback is provided to the user through a dedicated userfeedback device;

FIG. 12 depicts a schematic view of an exemplary gastric band systemincluding biomarker sensor feedback, where biomarker sensor feedback isused to automatically adjust a gastric band;

FIG. 13 depicts a schematic view of another exemplary gastric bandsystem including biomarker sensor feedback, where biomarker sensorfeedback is used to provide implant-originated feedback to a patient orclinician;

FIG. 14 depicts a schematic view of an exemplary drug infusion systemincluding biomarker sensor feedback, where biomarker sensor feedback isused to provide automatic adjustment of drug delivery by a drug infusiondevice;

FIG. 15 depicts a partial perspective view of the distal end of anexemplary harmonic surgical instrument with a harmonic blade having atherapeutic agent delivery feature;

FIG. 16 depicts a partial perspective view of the distal end of anotherexemplary harmonic surgical instrument with a harmonic blade having atherapeutic agent delivery feature;

FIG. 17 depicts a partial perspective view of the distal end of anotherexemplary harmonic surgical instrument with a harmonic blade having atherapeutic agent delivery feature;

FIG. 18A depicts a top view of the harmonic blade of the harmonicsurgical instrument of FIG. 17, in an inactive state;

FIG. 18B depicts a top view of the harmonic blade of the harmonicsurgical instrument, in an active state;

FIG. 19A depicts a side view of another exemplary harmonic blade havinga therapeutic agent delivery feature, in a distal position at a firstinstant while activated;

FIG. 19B depicts a side view of the harmonic blade of FIG. 19A, in aproximal position at a second instant while activated;

FIG. 19C depicts a side view of the harmonic blade of FIG. 19A, in theproximal position at a third instant while activated;

FIG. 20 depicts a cross-sectional end view of the harmonic blade of FIG.19A;

FIG. 21 depicts a perspective cross-sectional view of another exemplaryharmonic blade having a pair of therapeutic agent delivery features;

FIG. 22 depicts a perspective cross-sectional view of another exemplaryharmonic blade having a therapeutic agent delivery feature;

FIG. 23A depicts a top cross-sectional view of another exemplaryharmonic blade having a sheath and therapeutic agent delivery features,with the blade in a proximal position while activated;

FIG. 23B depicts a top cross-sectional view of the harmonic blade ofFIG. 23A, with the blade in a distal position while activated;

FIG. 24A depicts a top cross-sectional view of another exemplaryharmonic blade having a sheath and a therapeutic agent delivery feature,with the blade in a distal position while activated;

FIG. 24B depicts a top cross-sectional view of the harmonic blade ofFIG. 24A, with the blade in a proximal position while activated;

FIG. 25 depicts a partial perspective view of the distal end of anotherexemplary harmonic surgical instrument having a therapeutic agentdelivery feature adjacent to its harmonic blade;

FIG. 26 depicts a partial perspective view of the distal end of anotherexemplary harmonic surgical instrument with a clamp pad havingtherapeutic agent delivery features;

FIG. 27A depicts a top view of a therapeutic agent delivery feature ofthe clamp pad of FIG. 26, in a non-activated state;

FIG. 27B depicts a top view of the therapeutic agent delivery feature ofFIG. 27A, in an activated state;

FIG. 28 depicts a partial perspective view of the distal end of anotherexemplary harmonic surgical instrument with a clamp pad havingtherapeutic agent delivery features and a therapeutic agent cartridge;

FIG. 29 depicts a partial perspective view of the distal end of anotherexemplary harmonic surgical instrument with a clamp pad havingtherapeutic agent delivery features;

FIG. 30 depicts a partial perspective view of several examples oftherapeutic agent delivery features that may be incorporated into theclamp pad of FIG. 29;

FIG. 31 depicts a partial perspective view of several other examples oftherapeutic agent delivery features that may be incorporated into theclamp pad of FIG. 29;

FIG. 32 depicts a perspective perspective view of an exemplary harmonicsurgical instrument coupled with a therapeutic agent source for deliveryof the therapeutic agent through the harmonic surgical instrument;

FIG. 33 depicts a partial side view of an exemplary harmonic surgicalinstrument with therapeutic agent sources provided in a handle portion;

FIG. 34 depicts a partial side view of an exemplary harmonic surgicalinstrument with therapeutic agent sources provided in a handle portionand with a flow restriction feature also provided in the handle portion;

FIG. 35A depicts a side view of the flow restriction feature of FIG. 34in a first use position;

FIG. 35B depicts a side view of the flow restriction feature of FIG. 34in second and third use positions;

FIG. 36 depicts a partial side view of an exemplary harmonic surgicalinstrument with therapeutic agent sources provided in a handle portionand with a manual pump feature also provided in the handle portion;

FIG. 37 depicts a partial side view of an exemplary harmonic surgicalinstrument with therapeutic agent sources provided in a handle portionand with an automated pump feature also provided in the handle portion;

FIG. 38 depicts a side cross-sectional view of an exemplary structurethat may be incorporated into the automated pump feature of FIG. 37;

FIG. 39 depicts a side cross-sectional view of another exemplarystructure that may be incorporated into the automated pump feature ofFIG. 37;

FIG. 40 depicts a partial cross-sectional view of a patient's abdomenwith a therapeutic agent delivery device and a harmonic surgicalinstrument inserted through the abdominal wall;

FIG. 41 depicts a perspective view of an exemplary alternativetherapeutic agent delivery device;

FIG. 42 depicts a perspective view of an exemplary therapeutic agentdelivery pad; and

FIG. 43 depicts a cross-sectional view of a harmonic blade being used toactivate the therapeutic agent delivery pad of FIG. 42 against apatient's tissue.

The drawings are not intended to be limiting in any way, and it iscontemplated that various embodiments of the technology may be carriedout in a variety of other ways, including those not necessarily depictedin the drawings. The accompanying drawings incorporated in and forming apart of the specification illustrate several aspects of the presenttechnology, and together with the description serve to explain theprinciples of the technology; it being understood, however, that thistechnology is not limited to the precise arrangements shown.

DETAILED DESCRIPTION

The following description of certain examples of the technology shouldnot be used to limit its scope. Other examples, features, aspects,embodiments, and advantages of the technology will become apparent tothose skilled in the art from the following description, which is by wayof illustration, one of the best modes contemplated for carrying out thetechnology. As will be realized, the technology described herein iscapable of other different and obvious aspects, all without departingfrom the technology. Accordingly, the drawings and descriptions shouldbe regarded as illustrative in nature and not restrictive.

I. Definitions

Antibody as used herein includes polyclonal and monoclonal antibodies,single chain, chimeric and humanised antibodies, as well as antibodyfragments, whether produced by recombinant or proteolytic means. Theterm is also meant to include the products of any antibody-derivedexpression libraries, e.g. single-chain Fv or Fab fragment expressionlibraries.

The term “gene” has its meaning as understood in the art. However, itwill be appreciated by those of ordinary skill in the art that the term“gene” may include gene regulatory sequences (e.g., promoters,enhancers, etc.) and/or intron sequences. It will further be appreciatedthat definitions of gene include references to nucleic acids that do notencode proteins but rather encode functional RNA molecules such as tRNAsand miRNAs. For clarity, the term gene generally refers to a portion ofa nucleic acid that encodes a protein or functional RNA; however, theterm may optionally encompass regulatory sequences. In some cases, thegene includes regulatory sequences involved in transcription, or messageproduction or composition. In other examples, the gene comprisestranscribed sequences that encode for a protein, polypeptide or peptide.In keeping with the terminology described herein, an “isolated gene” maycomprise transcribed nucleic acid(s), regulatory sequences, codingsequences, or the like, isolated substantially away from other suchsequences, such as other naturally occurring genes, regulatorysequences, polypeptide or peptide encoding sequences, etc. In thisrespect, the term “gene” is used for simplicity to refer to a nucleicacid comprising a nucleotide sequence that is transcribed, and thecomplement thereof. As will be understood by those in the art, thisfunctional term “gene” includes both genomic sequences, RNA or cDNAsequences, or smaller engineered nucleic acid segments, includingnucleic acid segments of a non-transcribed part of a gene, including butnot limited to the non-transcribed promoter or enhancer regions of agene. Smaller engineered gene nucleic acid segments may express, or maybe adapted to express using nucleic acid manipulation technology,proteins, polypeptides, domains, peptides, fusion proteins, mutantsand/or such like.

Markers/biomarkers may include genes, proteins, metabolites (e.g.,vitamins, etc.), and the like. By way of example only, amarker/biomarker may also include any molecule derived from a gene,e.g., a transcript of the gene, a sense (coding) or antisense(non-coding) probe sequence derived from the gene, or a full length orpartial length translation product of the gene or an antibody thereto,which can be used to monitor a condition, disorder, disease, or thestatus in the progression of a process, e.g. a healing process or theprogression in a disease. Biomarkers may be labeled to assist detection,the choice of label being directed by the nature of the biomarker.Suitable labels may include radionucleotides, enzymes, fluorescent,chemiluminescent, or chromogenic agents as well as substrates,cofactors, inhibitors, magnetic particles. Other suitablemarkers/biomarkers will be apparent to those of ordinary skill in theart in view of the teachings herein.

RNA refers to a molecule comprising at least one ribonucleotide residue.The term “ribonucleotide” means a nucleotide with a hydroxyl group atthe 2′ position of a beta-D-ribofuranose moiety. The terms includedouble-stranded RNA, single-stranded RNA, isolated RNA such as partiallypurified RNA, essentially pure RNA, synthetic RNA, recombinantlyproduced RNA, as well as altered RNA that differs from naturallyoccurring RNA by the addition, deletion, substitution and/or alterationof one or more nucleotides. Such alterations can include addition ofnon-nucleotide material, such as to the end(s) of an RNAi agent orinternally, for example at one or more nucleotides of the RNA.Nucleotides in the RNA molecules of the instant technology can alsocomprise non-standard nucleotides, such as non-naturally occurringnucleotides or chemically synthesized nucleotides or deoxynucleotides.These altered RNAs can be referred to as analogs or analogs of naturallyoccurring RNA.

It should also be understood that the term “therapeutic agent” herein isintended to broadly encompass various kinds of agents and medicalsubstances, including but not limited to gene therapies, stem celltherapies, hemostatic agents, healing agents, adhesives, sealants,anti-bacterial agents, infection-resistant agents, analgesics,conventional pharmaceutical drugs, other chemicals, liquids, powders,etc. It should also be understood that the use of the term “therapeuticagent” herein is not intended to demonstrate that concepts describedherein are limited to only agents that are used for therapeuticpurposes. The term “therapeutic agent” as used herein is intended toencompass various kinds of medical agents/substances, including but notlimited to those used for preventative, prophylactic, and/or remedialpurposes, and including those used for various purposes that might notbe considered “therapeutic” in a traditional sense of the word“therapeutic.” Various kinds of agents/substances that may be used inaccordance with the teachings herein, as well as various purposes forwhich such agents/substances may be used, will be apparent to those ofordinary skill in the art in view of the teachings herein. All suchagents/substances/purposes are intended to be encompassed by the use ofthe term “therapeutic agent” herein.

II. Overview

A. Principles of Biomarkers

Examples described herein relate to a principle that the expression ofcertain biomarkers may be different in wound tissues as compared to theexpression of those same biomarkers in healthy tissues. Moreparticularly, examples described herein relate to methods and probes forinvestigating and evaluating the presence of RNA species that aredifferentially expressed in wound and normal tissue (e.g., in realtime)as a function of the type of surgical device used to make the incisionand/or as a function of other factors. Examples described herein alsorelate to the use of specific genes and their translation products tomonitor wound healing and/or to detect disorders or diseasescharacterized by impaired or excessive wound healing. Examples describedherein also relate to methods for the evaluation and identification ofcompounds useful for the treatment of wounds, inflammation and woundhealing disorders, compounds identified by such screening methods, theuse of such compounds in the manufacture of medicaments or in methods ofmedical treatment. In addition, examples described herein providemethods to assess the utility and efficiency of surgical cutting devicesby monitoring levels of biomarkers which are indicative of hemostasis,inflammation, chemotaxis, immune response, fibrosis and/or scarremodeling. Still other examples of how biomarkers may be used inconjunction with various surgical devices are described herein.

Many medical procedures require surgery to be performed in which tissuesare cut, blood vessels are coagulated, other tissue is excised, and thecut is subsequently closed and allowed to heal. A surgical incision byits very nature may cause a wide range of tissue damage. Where themedical procedure requires some type of incision, the surgeon may have achoice of the method of incision and method of coagulation control andthus may choose a surgical device that provides optimum hemostaticcontrol with minimal tissue damage. One type of device for surgicalcutting is the steel scalpel. The scalpel may cause relatively minimaltissue damage. However since a steel scalpel may provide almost nohemostatic control, other means may need be taken to close blood vesselsand stop bleeding. One method developed to both cut and coagulate iselectrosurgery. In this method, an electric current is passed throughthe tissue, thereby heating the tissue to a high temperature. This heatboth cuts and coagulates the tissue via protein denaturation. Althoughelectrosurgery may be viewed as an advance over the steel scalpel interms of hemostasis, there may ultimately be more tissue damage due tothe high heat of electrosurgical device which may lead to increasedinflammation, additional pain and a longer period of wound healing.

Some other devices may offer effective cutting and hemostasis withrelatively reduced tissue damage. Some such devices include “Harmonic”ultrasonic surgical devices provided by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio, such as those provided under the names Harmonic FOCUS,Harmonic WAVE, Harmonic ACE, and Harmonic SYNERGY to name a few. Thesedevices operate via high-frequency (e.g., 55.5 kHz) oscillation of ablade that both cuts and coagulates tissue. Coagulation is achievedthrough heating which is in turn induced by the mechanical vibratoryaction of the blade. Use of such energized surgical techniques mayresult in denatured or degraded proteins. A potential side benefit ofultrasonic devices is that they can, in certain configurations, be usedto liquefy and aerosolize tissues making direct sampling for biomarkerseasily obtainable and with little degradation of the final protein ormRNA. Ultrasonic devices may also create micropores in the walls oftissue cells in a patient (“sonoporation”), which may facilitatetransfer of genes and/or other agents into the patient's cells as willbe described in greater detail below.

The central response to tissue damage is provided via genetic control.The DNA of various response genes are translated into mRNA which canthen induce the production of a corresponding protein. Both the mRNA andprotein may be found to be useful biomarkers. Pre-existing proteins mayalso be damaged by surgical intervention, and hence these proteins ortheir remnants may be utilized as biomarkers for tissue damage.

Poor hemostatic control may lead to increased bleeding and tissuedamage. Likewise, excessive hemostatic control (e.g., via extremeheating) may injure tissue unnecessarily. In either case, tissue damagemay result in increased inflammation, pain, scar formation and a longerperiod of scar remodeling. Therefore, there may be a need for improvedsurgical devices that cause less trauma to neighboring tissue and formethods to evaluate such devices.

To assist in evaluating the extent of trauma caused by a surgicaldevice, biomarkers may be chosen from the different phases of the woundhealing process. The first phase of wound healing, hemostasis, may occurimmediately after incision. During hemostasis the bleeding may becontrolled by natural coagulation, suture, or heat denaturation ofproteins. A high level of heat may lead to a large residue of hemoglobinfragments, and it is believed that these fragments may be suitablebiomarkers for quantitatively assessing the trauma inflicted by surgicaldevices. Other biomarkers that may be useful at this stage of woundhealing may include components of platelets and early mediators of theinflammatory response.

Biomarkers such as hemoglobin fragments, platelet components andinflammatory mediators may be viewed as indicators that the tissue hasbeen injured and higher levels may in turn reflect a more damagingsurgical device. On the other hand, certain biomarkers may be viewed asindicative of the healing process, and a less damaging surgical devicemay enhance the presence of these particular markers. Examples includealbumin, transferrin and vimentin. These proteins are believed to aid inthe healing process. It is believed that an assay for these proteins maybe used to distinguish the amount of tissue damage inflicted bydifferent surgical devices, with a “better” surgical device reducing thelevel of these proteins by a smaller amount.

Inflammation constitutes the second phase of wound healing. In thisphase, the immune system sends out a response to prevent infection.Chemokines, such as CXCL8 (IL-8), call in immune cells, such asneutrophils and macrophages. A higher level of chemokines may generallyreflect greater tissue damage from a particular surgical device andlower levels of chemokines may reflect a less damaging surgical device.

The inflammation stage is followed by a proliferation phase. At thispoint cytokines, such as TGF-β, induce the proliferation of fibroblaststhat produce collagen. Since TGF-β is produced at several stages of thewound healing process and at varying levels, it may in general not be asgood a biomarker as the others mentioned. Since the proliferation phasefollows the inflammation phase, use of biomarkers at this point maynecessarily be delayed compared to biomarkers that occur earlier in thewound healing process.

The final phase of wound healing is remodeling in which collagen levelsare decreased, the wound breaking strength is increased and the scarslowly disappears. Since this is the last and slowest phase of woundhealing, biomarkers taken from it may be less useful in quicklyassessing the trauma inflicted by a surgical device. Furthermore,biomarkers from the initial phases may be more likely to be predictiveof the intensity and length of the later phases. Greater hemostasistrauma or inflammation may lead to more fibroblast proliferation,collagen deposition, and longer time for scar remodeling.

It should also be understood that when an incision or other biologicalalteration is made by a surgical instrument or other type of medicaldevice, the resulting changes in biomarker expressions may have acascading effect. For instance, the biological alteration may initiallyproduce a first change in one or more biomarkers; while the first changein one or more biomarkers may lead to a second change in another one ormore biomarkers; and so on. By way of example only, a biologicalstimulus might include infection by a pathogenic organism, such as avirus or bacteria. The organism could be sensed by specific receptors,such as Toll-like Receptors (TLR) or Retinoid-Inducible Gene-1 (RIG-1).These sensors can then initiate a cascade of chemical and physiologicalresponses in the immune system by secreting cytokines and chemokines,such as interferon and IL-8. The chemokines will attract immune cells,such as macrophages and granulocytes, that will further secretecytokines and chemokines, and may also initiate an inflammatory reactionthat may be involve prostaglandins and leukotrienes. As a defensivemeasure the cascade may unleash a respiratory burst of highly oxidizingspecies, such as peroxides and superoxide radicals, which can destroypotential pathogens, but may also cause substantial tissue injury.

In some settings, affirmative steps may be taken (before, during, and/orafter a surgical procedure) to block or restrict changes or expressionsof biomarkers that might otherwise occur as a result of a surgicalprocedure. Thus, these affirmative steps may alter or even dictate thesequence or characteristics of the “biomarker cascades” referred toabove. For example, if the biomarker cascade involves an extremerespiratory burst of free radicals, then therapeutic treatment withantioxidants may be beneficial. If substantial inflammatory biomarkersare observed, then corticosteroids may be applied to limit the immuneresponse. In chronic wound healing, m-RNA blocking strategies forTGF-beta or other biomarkers may prevent excessive granulation tissueand keloid formation. Other examples of how preparatory steps,therapeutic steps, or other kinds of steps may be taken in response tobiomarker expressions are described elsewhere herein; while still otherexamples will be apparent to those of ordinary skill in the art in viewof the teachings herein.

There are numerous methods of improving wound healing once injury to thetissue has occurred. Some such approaches involve nutritional and/ortherapeutic treatments. For instance, U.S. Pat. No. 6,187,743, entitled“Composition and Method for Enhancing Wound Healing,” issued Feb. 13,2001, the disclosure of which is incorporated by reference herein,discloses compositions and methods used to treat a pre-existing wound;but does not disclose how to minimize the trauma from an iatrogenicwound, nor does it disclose relevant biomarkers that may be used toassess the trauma inflicted by surgical devices or the design andselection of surgical instruments used for cutting the tissue.

Methods have also been described wherein biomarkers are used to assesswound healing. Examples include U.S. Pub. No. 2004/0038292, entitled“Wound Healing Biomarkers,” published Feb. 26, 2004, the disclosure ofwhich is incorporated by reference herein; and U.S. Pub. No.2005/0287535, entitled “Biomarkers for Wound Healing,” published Dec.29, 2005, the disclosure of which is incorporated by reference herein.However, these applications did not describe the use of biomarkers inthe context of real-time surgical assessments and/or as a guide indetermining the best device to be used for a particular procedure wherea cut to the tissue is necessitated.

B. Monitoring of Biomarkers

Examples described herein are based on the analysis of biomarkers (e.g.,genes and proteins), the expression of which is upregulated ordownregulated during a wound healing response, occurring with or withoutthe inflammatory response and usually occurring in healing wounds. It isbelieved that the presence (or absence) of certain biomarkers may beused to monitor the progression of wound healing; and in some casesthese biomarkers may be monitored in real time, during the surgicalprocedure. Examples described herein also provide markers that areuseful in monitoring, for example, the state of healing of a wound.These markers may be used more generally for monitoring diseases ordisorders characterized by impaired or by excessive wound healing. Inaddition, examples described herein provide markers for woundinflammation. These markers may be useful in the clinical assessment ofthe progress of healing and may be used to aid in the selection of theappropriate therapeutic intervention.

As described elsewhere herein, various proteins may serve as usefulbiomarkers. Since protein is manufactured based on instructions frommRNA, the appearance of protein lags behind that of the mRNA.Furthermore, there are other regulatory processes involved, so that ahigh level of mRNA does not necessarily correlate with a high level ofits corresponding protein. Therefore it may be useful to measure mRNAlevels, protein levels, or both. It should also be understood thatdifferent biomarkers may be expressed during different time frames inresponse to a wound or other biological condition. For instance, somebiomarkers may be expressed immediately, others within hours, otherswithin a week, others within several weeks, etc. Thus, in someinstances, it may be useful to tailor biomarker monitoring based ontiming, such as to only look for certain biomarkers during certain timeframes. Similarly, selections of biomarkers for monitoring may be basedon factors such as the location in the patient's anatomy where the woundhas been or will be inflicted, the type of device that is inflicting thewound, the vehicle used to convey the biomarkers to the monitoringinstrument, and/or various other factors.

The expression levels of biomarkers may be quantified by any assayavailable to one skilled in the art and/or using any other suitabletechniques as will be apparent to those of ordinary skill in the art inview of the teachings herein. For instance, a measurement may be takendetecting the presence or absence of the biomarkers(s), quantifying theamount of marker(s), and qualifying the type of biomarker. The biomarkermeasurement may be made for instance, by using a biochip array. In someexamples, the biochip array is an antibody chip array, tissue chiparray, protein chip array, or a peptide chip array. In some otherexamples, the biochip array is a nucleic acid array. In still otherexamples, at least one biomarker capture reagent is immobilized on thebiochip array. In still other examples, the protein biomarkers aremeasured by immunoassay. In addition, biomarker expression levels may bequantified by a hybridization assay of RNA obtained from the woundtissue sample to a probe complementary to a particular receptor, forinstance, IL8 receptor. In other examples, the expression levels mayalso be quantified by amplification of wound tissue sample RNA. Theexpression levels may also be quantified by immunoassay of the woundtissue sample using an antibody directed against a particular receptor,for example, the IL8 receptor.

Another tool that may be useful in identifying biomarkers generatedin-situ during surgery is mass spectrometry, which may quickly identifyany molecule in a sample by measuring its mass and charge. Morespecifically, DESI (desorption electrospray ionization) may be used,whereby a sample collector may work in open air and leave tissue intact.In some versions, DESI may be used with commercial mass spectrometersand may monitor tissues in real-time during the surgery. This techniquemay provide one with the ability to identify a broad spectrum ofmolecules in a tissue or even inside a cell and may give an intimatelydetailed picture the activities and disease state of the tissue and/orcells in question during surgery.

Molecular cell bioengineering may also be used in monitoring andidentifying biomarkers that are generated in-situ during surgery. Thismethod uses computational models for receptor regulation of cellfunction by exploiting techniques of molecular biology to alterparameters characterizing receptor or ligand properties inwell-characterized cell systems. Molecular cell bioengineering developsa quantitative understanding of cell function in terms of fundamentalmolecular properties and includes important aspects of receptor-mediatedregulation of mammalian blood and tissue cell behavioral functions suchas proliferation, adhesion, migration, differentiation, and death.Quantitative experimental assays monitoring for the presence or absenceof key biomarkers may be used to measure cell functions, receptor/ligandinteraction parameters, and signaling network dynamics during surgery.

The presence (or absence) of certain biomarkers may be used to adjustthe monitoring, administration, and/or planning of particulartherapeutics or actives during a surgical procedure. “Active” in thissense may include a variety of things, including but not limited to genetherapies, stem cell treatments, conventional pharmaceutical drugs, etc.The analysis of these biomarkers may also be evaluated in real-time inorder to adjust the administration of any active that may be neededand/or to alter the surgical parameters. In addition, through themonitoring of the biomarkers, examples described herein may provide amethod of identifying an active (or actives) useful for treating thewound tissue during the surgical procedure as well as after theprocedure to aid in reduced healing time for the patient. Biomarkers mayalso be used to gauge the relative damage of different surgicalinstruments that are used to make the incisions during the surgery. Inaddition, the sensitivity of this method may be sufficient to not onlymonitor the damage produced by a particular surgical device, but to alsodistinguish between different surgical devices and the desirability ofone device versus another for a particular procedure. The differencesobserved can then be used to further improve the efficiency of thesurgical device, and in turn, lessen the patient's trauma.

In some versions, one or more elements of a biomarker monitoringapparatus are incorporated into a wound dressing. For instance, thewound dressing may include a one or more biomarker measuring devicesthat contact the wound while the wound dressing still serves a purposeas a wound dressing. Such an apparatus may allow clinicians tointerrogate the one or more biomarker measuring devices, either uponremoval of the wound dressing or without requiring the wound dressing tobe removed.

A merely illustrative example of a process that may be carried out tomonitor biomarkers and use biomarker data is illustrated in FIG. 1. Asshown in block (10), a mist at a wound site is evacuated to drawbiomarkers from the patient for processing. In some versions, includingsome of those described in greater detail below, such a mist is producedby a harmonic surgical instrument that is used to create the wound aspart of a surgical procedure. Those of ordinary skill in the art willappreciate that such a mist or smoke may be produced anyway as a matterof course during surgical use of a conventional harmonic device, suchthat the process illustrated in FIG. 1 simply draws off at least part ofthat expected (and otherwise wasted) mist in order to process biomarkerscontained in the mist. As will also be described in greater detailbelow, such a mist may be evacuated using suction created by a vacuumsource that is in fluid communication with a port at or near the endeffector of the harmonic surgical instrument.

Continuing to block (20) of FIG. 1, the evacuated mist is filtered anddiluted with saline or some other fluid medium. As part of the filteringrepresented by block (20), the mist may be sieved ultrasonically,electrostatically, both, and/or otherwise filtered. Optionally,biomarkers in the mist may be cleaved with one or more enzymes as shownin block (30) of FIG. 1. Suitable situations in which such cleaving maybe desirable, as well as suitable enzymes that may be used in this partof the process, will be apparent to those of ordinary skill in the artin view of the teachings herein. After cleaving by enzymes, the mistwith biomarkers is flowed over a sensor as shown in block (40) ofFIG. 1. Various examples of suitable sensors that may be used at thisstage are described elsewhere herein, while still other examples ofsuitable sensors will be apparent to those of ordinary skill in the artin view of the teachings herein. It should also be understood thatvarious types of sensors may be used in any given process, such as byusing different sensors to pick up different biomarkers. For instance,any one or more biomarkers referred to herein, including but not limitedto genomes or proteomes, may be picked up by one or more sensors as partof the process shown in FIG. 1, among other biomarkers. As shown inblock (50), the next stage of the process in the present example is toobtain one or more readings from the sensor(s) and process suchreading(s) in one or more selected ways.

The process illustrated in FIG. 1 shows several options for actions thatmay be taken in response to readings obtained from a biomarker sensor.For instance, as shown in block (60), a particular therapy (e.g.,therapeutic agent, therapeutic process, etc.) may be selected andadministered based on readings obtained from a biomarker sensor. Varioussuitable ways in which such therapy may be selected and administeredbased on biomarker data are described elsewhere herein, while stillother examples of suitable ways in which such therapy may be selectedand administered based on biomarker data will be apparent to those ofordinary skill in the art in view of the teachings herein. As shown inblock (70), a particular device (e.g., surgical instrument, medicalimplant, wound dressing, etc.) may be selected based on readingsobtained from a biomarker sensor. Again, various suitable ways in whicha device may be selected based on biomarker data are described elsewhereherein, while still other examples of suitable ways in which a devicemay be selected based on biomarker data will be apparent to those ofordinary skill in the art in view of the teachings herein. As shown inblock (80), one or more operating parameters of a device (e.g., surgicalinstrument, medical implant, wound dressing, etc.) may be adjusted basedon readings obtained from a biomarker sensor. Again, various suitableways in which operating parameters of a device may be adjusted based onbiomarker data are described elsewhere herein, while still otherexamples of suitable ways in which operating parameters of a device maybe adjusted based on biomarker data will be apparent to those ofordinary skill in the art in view of the teachings herein. As shown inblock (90), the technique by which a device (e.g., surgical instrument,medical implant, wound dressing, etc.) is used may also be adjustedbased on readings from a biomarker sensor. Yet again, various suitableways in which the technique by which a device is used may be adjustedbased on biomarker data are described elsewhere herein, while stillother examples of suitable ways in which the technique by which a deviceis used may be adjusted based on biomarker data will be apparent tothose of ordinary skill in the art in view of the teachings herein.

It should be understood that the reactions to biomarker data shown inblocks (60, 70, 80, 90) of FIG. 1 are merely illustrative examples.Various other types of reactions to biomarker data may be taken inaddition to or in lieu of any of those shown in blocks (60, 70, 80, 90).Similarly, it should be understood that the process shown in FIG. 1 ismerely one example. The process shown in FIG. 1 may be varied innumerous ways, including but not limited to supplementing the processwith steps not shown in FIG. 1, substituting one or more steps shown inFIG. 1 with one or more other steps, omitting one or more of the stepsshown in FIG. 1, etc. Additional examples of how biomarkers may bedetected, quantified, qualified, etc. will be described in greaterdetail below (e.g., section V.A., below), while various other exampleswill be apparent to those of ordinary skill in the art in view of theteachings herein. Similarly, various ways in which biomarker data may beused will be described in greater detail below (e.g., section V.B.through section V. C., below), while various other examples will beapparent to those of ordinary skill in the art in view of the teachingsherein.

C. Examples of Biomarkers

Specific examples of biomarkers that may be detected/monitored/used/etc.in accordance with the teachings herein are given in Tables 1-4. Table 1provides a list of genes that are upregulated after the trauma ofsurgery. These genes or their associated proteins may be used todetermine the degree of trauma resulting from a particular medicaldevice. An increase in the level of gene expression or the amount of itsassociated protein indicates greater tissue damage from the medicaldevice. It should be understood that a relatively high amount of tissuedamage may be due to properties of the medical device itself, the way inwhich the medical device was used, and/or a particular susceptibility ofthe patient in/on which the medical device was used, among otherpotential factors. In some settings, a lower level of gene expression orthe amount of its associated protein can therefore be used to identify aless traumatic, hence “superior” surgical cutting instrument and/ortechnique. In addition or in the alternative, a higher level of geneexpression or the amount of its associated protein may be used toidentify a higher susceptibility of a particular patient to tissuedamage; and such information may thus be used to modify the selection ofa medical device for use on the patient, to modify the way in which amedical device is used in/on the patient, and/or to select thetype/amount of one or more agents to be administered to the patient atthe wound site.

TABLE 1 Upregulated Genes No. Acronym Gene description 1 CXCL6Granulocyte chemotactic protein 2 (GCP-2) 2 IL8 Interleukin-8 3 ARG1Arginase 1 4 SERPINB2 Plasminogen activator inhibitor-2 (PAI-2) 5 CXCL2Macrophage inflammatory protein-2-alpha (MIP2-alpha) 6 FAM81B Familywith sequence similarity 81, member B 7 PPBP Platelet basic protein(CXCL7) 8 PF4 Platelet factor 4 (CXCL4) 9 GPR68Sphingosylphosphorylcholine receptor 10 TNC Tenascin 11 MARCO Macrophagereceptor with collagenous structure 12 PRSS35 Protease, serine, 35 13CYP1B1 Cytochrome P450 1B1 14 CA12 Carbonic anhydrase XII 15 IL6Interleukin-6 16 ALDH9A1 Aldehyde dehydrogenase 9 family, member A1 17SDS L-serine dehydratase 18 IL1RN Interleukin-1 receptor antagonistprotein 19 PTX3 Pentaxin-related protein 20 SELE E-selectin 21 ADFPAdipophilin 22 TIMP1 Metalloproteinase inhibitor 1 23 Q6ZUM6 Dynein,cytoplasmic, heavy polypeptide 2 24 IDH2 Isocitrate dehydrogenase 25SERPINE1 Plasminogen activator inhibitor-1 26 ANGPTL4Angiopoietin-related protein 4 27 CYR61 Cysteine-rich, angiogenicinducer, 61 28 CXCL14 Small inducible cytokine B14 29 MMP1 Matrixmetalloproteinase-1 30 NPM3 Nucleoplasmin 3 31 CYP3A4 Cytochrome P4503A4 32 HLA-DRB4 MHC class I antigen DRB1*4 33 FOS Cellular oncogene fos34 AMELX Amelogenin, X isoform 35 FRYL FRY-like 36 RRM2Ribonucleoside-diphosphate reductase M2 chain 37 CDKAL1 CDK5 regulatorysubunit associated protein 1 38 S100A9 Calgranulin B 39 PCP4L1 Purkinjecell protein 4 like 1 40 SFRP2 Secreted frizzled-related protein 2 41THBS1 Thrombospondin 1 42 AQN1 Spermadhesin 43 TCA_ T-cell receptoralpha chain C region HUMAN 44 HMOX1 Heme oxygenase 1 45 TMEM49Transmembrane protein 49 46 FZD1 Frizzled 1 47 KRT1 Keratin, type IIcytoskeletal 1 48 CCNB1 G2/mitotic-specific cyclin B1 49 LIF Leukemiainhibitory factor precursor 50 CCL2 Monocyte chemotactic protein 1(MCP-1) 51 ACTG2 Actin, gamma-enteric smooth muscle 52 MIG6_Mitogen-inducible gene 6 protein HUMAN 53 SLC16A3 Monocarboxylatetransporter 4 54 MMP7 Matrilysin 55 MAP3K8 Mitogen-activated proteinkinase kinase kinase 8 56 OLFM3 Olfactomedin 3 57 KCNH1 Potassiumvoltage-gated channel subfamily H member 1 58 RIMS1 Regulating synapticmembrane exocytosis protein 1 59 CCDC99 Coiled-coil domain containing 9960 SMARCAL1 SWI/SNF-related matrix-associated actin- dependent regulatorof chromatin a-like 1 61 ARL7 ADP-ribosylation factor-like protein 7 62CKAP4 Cytoskeleton-associated protein 4 63 KIAA0101 HCVNS5A-transactivated protein 9 64 NP_077001 XTP3-transactivated protein A65 PLS1 Intestine-specific plastin 66 SLC2A14 Glucose transporter 14 67TNFAIP1 Tumor necrosis factor, alpha-induced protein 1, endothelial 68CLECSF5 C-type lectin, superfamily member 5 69 BUB1 Mitotic checkpointserine/threonine-protein kinase 70 CSRP2 Cysteine and glycine-richprotein 2 71 SKA1 Spindle and KT associated 1 72 DLG7 Discs, largehomolog 7 73 BIRC5 Apoptosis inhibitor survivin 74 LIPG Endotheliallipase 75 CENPE Centromeric protein E 76 MCAM Cell surface glycoproteinMUC18 77 POLQ DNA polymerase theta 78 UCK2 Uridine-cytidine kinase 2 79CTSL Cathepsin L 80 HPSE Heparanase 81 SHCBP1 SHC SH2-domain bindingprotein 1 82 HAS2 Hyaluronan synthase 2 83 STK6 Serine/threonine-proteinkinase 6 84 ETV6 Transcription factor ETV6 85 KRT17 Keratin, type Icytoskeletal 17 86 KRT5 Keratin, type II cytoskeletal 5 87 KRTAP3-3Keratin associated protein 3-3 88 SCGB2A1 Mammaglobin B (Mammaglobin 2)89 CBR1 Carbonyl reductase [NADPH] 1 90 KRTAP3-1 Keratin associatedprotein 3-1 91 KRT14 Keratin, type I cytoskeletal 14 92 LTFLactotransferrin (Lactoferrin) 93 CHIA Acidic mammalian chitinase 94KRTHA2 Keratin, type I cuticular HA2 95 TDO2 Tryptophan 2,3-dioxygenase96 KRT10 Keratin, type I cytoskeletal 10 97 KRTAP1-5 keratin associatedprotein 1.5 98 KRTAP2-4 keratin associated protein 2-4 99 DSPDesmoplakin 100 SFN 14-3-3 protein sigma (Stratifin) 101 AP1S3Adapter-related protein complex 1 sigma 1C 102 PERP PERP, TP53 apoptosiseffector

Although either the gene mRNA or the associated proteins may be used, insome cases it may be preferable to use the mRNA because the level of theproteins on this list may be at very low levels, and hence may bedifficult to assay accurately. Of course, certain assay techniques maybe suitable for accurately assaying very low levels of proteins. Itshould also be understood that the listing of Table 1 is not intended tobe exhaustive, as other genes may be upregulated after the trauma ofsurgery.

Table 2 provides a list of genes that are downregulated after the traumaof surgery. These genes or their associated proteins may be used todetermine the degree of trauma resulting from the use of a particularmedical device in making an incision. A decrease in the level of geneexpression or the amount of its associated protein indicates greatertissue damage from the medical device. A less depressed level of geneexpression or the amount of its associated protein can therefore be usedto identify a less traumatic, and hence less damaging surgical cuttinginstrument and/or technique. In addition or in the alternative, a lessdepressed level of gene expression or the amount of its associatedprotein may be used to identify a reduced susceptibility of a particularpatient to tissue damage; and such information may thus be used tomodify the selection of a medical device for use on the patient, tomodify the way in which a medical device is used in/on the patient,and/or to select the type/amount of one or more agents to beadministered to the patient at the wound site.

TABLE 2 Downregulated Genes No. Acronym Gene description 1 PON3 Serumparaoxonase/lactonase 3 2 MYOC Myocilin 3 AGT Angiotensinogen 4 CA3Carbonic anhydrase III 5 EGF Pro-epidermal growth factor precursor 6CYP2A13 Cytochrome P450 2A13 7 FTHFD 10-formyltetrahydrofolatedehydrogenase 8 PPP1R1A Protein phosphatase inhibitor 1 9 ELOVL6 ELOVLfamily member 6, elongation of long chain fatty acids 10 KERA Kerato can11 BRUNOL4 Bruno-like 4, RNA binding protein 12 FASN Fatty acid synthase13 KCNS1 Potassium voltage-gated channel subfamily S member 1 14 CILPCartilage intermediate layer protein 15 AUTS2 Autism susceptibility gene2 protein 16 CDO1 Cysteine dioxygenase type I 17 GAP43 Neuromodulin 18ALDOC Fructose-bisphosphate aldolase C 19 LEP Leptin 20 DDO D-aspartateoxidase 21 CYP4F3 Cytochrome P450 4F3 22 SCD Acyl-CoA desaturase 23SLC36A2 Solute carrier family 36, member 2 24 GPR120 G protein-coupledreceptor 120 25 ME1 NADP-dependent malic enzyme 26 TMEFF2 Transmembraneprotein with EGF-like and two follistatin-like domains 27 KNTC1Kinetochore-associated protein 1 28 CES3 Liver carboxylesterase 1 29TTC36 Tetratricopeptide repeat domain 36 30 DAXX Death domain-associatedprotein 6 31 RBP4 Plasma retinol-binding protein 32 LPL Lipoproteinlipase 33 PGLYRP2 N-acetylmuramoyl-L-alanine amidase 34 ADHFE1 Alcoholdehydrogenase, iron containing, 1 35 LNP Lunapark 36 RNF180 Ring fingerprotein 180 37 GSN Gelsolin 38 G0S2 Lymphocyte G0/G1 switch protein 2 39APCDD1 Adenomatosis polyposis coli down-regulated 1 40 PNPLA7Patatin-like phospholipase domain containing 7 41 CYP4B1 Cytochrome P4504B1 42 DGAT2 Diacylglycerol O-acyltransferase homolog 2 43 HSPA12A Heatshock 70 kDa protein 12A 44 PDE5A cGMP-specific 3′,5′-cyclicphosphodiesterase 45 DGKB Diacylglycerol kinase, beta 46 SNTB1Beta-1-syntrophin 47 PPAP2A Lipid phosphate phosphohydrolase 1 48 PAQR6Progestin and adipoQ receptor family member VI isoform 1 49 ADR2Adiponectin receptor protein 2 50 ATP6V0A4 Vacuolar proton translocatingATPase 116 kDa subunit a isoform 4 51 ACAS2 Acetyl-coenzyme Asynthetase, cytoplasmic 52 ACACA Acetyl-CoA carboxylase 1 53 COL21A1Alpha 1 type XXI collagen 54 MAL2 MAL2 protein 55 SAL1 Salivarylipocalin 56 PPL Periplakin 57 ADORA1 Adenosine A1 receptor 58 DRR1 DRR1protein 59 GRPEL2 GrpE protein homolog 2, mitochondrial 60 FXYD1Phospholemman 61 LTBP4 Latent transforming growth factor beta bindingprotein 4 62 ANK3 Ankyrin 3 63 ACDC Adiponectin 64 OXCT1Succinyl-CoA:3-ketoacid-coenzyme A transferase 1, mitochondrial 65 TNATetranectin 66 CNTN1 Contactin 67 PSAT1 Phosphoserine aminotransferase68 MUM1L1 Melanoma associated antigen (mutated) 1-like 1 69 PC Pyruvatecarboxylase, mitochondrial 70 MFAP5 Microfibrillar-associated protein 5precursor 71 NTRK2 BDNF/NT-3 growth factors receptor 72 OPCML Opioidbinding protein/cell adhesion molecule 73 CITED1 Cbp/p300-interactingtransactivator 1 74 BCHE Cholinesterase 75 PPP1R1B Dopamine- andcAMP-regulated neuronal phosphoprotein 76 ARL4A ADP-ribosylationfactor-like protein 4A 77 LPIN1 Lipin 1 78 NAALADL2 N-acetylatedalpha-linked acidic dipeptidase 2 79 ADAMTS19 A disintegrin andmetalloproteinase with thrombospondin motifs 19 80 Q8WTR7 Zinc fingerprotein 473 81 PLAC1 Placenta-specific 1 82 ZFPM2 Zinc finger proteinZFPM2 83 LHCGR Lutropin-choriogonadotropic hormone receptor 84 EFHC2EF-hand domain (C-terminal) containing 2 85 ADAMTSL3 A disintegrin-likeand metalloprotease domain with thrombospondin type I motifs-like 3 86CXCL9 Gamma interferon induced monokine 87 GPD1 Glycerol-3-phosphatedehydrogenase [NAD+], cytoplasmic 88 SGK2 Serine/threonine-proteinkinase 89 ZC3H11A Zinc finger CCCH domain-containing protein 11A 90 CRB1Crumbs protein homolog 1 91 F5 Coagulation factor V 92 RBED1 RNA bindingmotif and ELMO domain 1 93 CAMK2N1 calcium/calmodulin-dependent proteinkinase II 94 CABC1 Chaperone-activity of bc1 complex-like, mitochondrial95 MORF4L1 Transcription factor-like protein MRG15 96 SPARCL1 SPARC-likeprotein 1 97 HPGD 15-hydroxyprostaglandin dehydrogenase 98 HLF Hepaticleukemia factor 99 PROM1 Prominin 1 100 LPIN1 Lipin 1 101 ISLRImmunoglobulin superfamily containing leucine- rich repeat 102 FMO1Dimethylaniline monooxygenase 103 SGCD Delta-sarcoglycan 104 UNC93AUNC-93 homolog A 105 PSPHL L-3-phosphoserine phosphatase 106 EZH2Enhancer of zeste homolog 2 107 CASC1 Cancer susceptibility candidate 1108 COL14A1 Collagen, Type XIV, Alpha-1 109 RUFY1 RUN and FYVE domaincontaining protein 1 110 RBP1 Retinol-binding protein I, cellular 111THSD2 Thrombospondin, type I, domain containing 2 112 GPT Alanineaminotransferase 113 SLC27A6 Solute carrier family 27 (fatty acidtransporter), member 6 114 SETBP1 SET-binding protein 115 ME1NADP-dependent malic enzyme 116 FASN Fatty acid synthase

Although either the gene mRNA or the associated proteins may be used, insome cases it may be preferable to use the mRNA because the level of theproteins on this list may be at very low levels, and hence may bedifficult to assay accurately. Again, though, certain assay techniquesmay be suitable for accurately assaying very low levels of proteins. Itshould also be understood that the listing of Table 2 is not intended tobe exhaustive, as other genes may be downregulated after the trauma ofsurgery.

Table 3 provides a listing of proteins that are increased after thetrauma of surgery. These proteins may be used to determine the degree oftrauma resulting from the use of a particular medical device in makingan incision. An increase in the level of the protein indicates greatertissue damage from the medical device. In addition or in thealternative, an increase in the level of the protein may be used toidentify a higher susceptibility of a particular patient to tissuedamage; and such information may thus be used to modify the selection ofa medical device for use on the patient, to modify the way in which amedical device is used in/on the patient, and/or to select thetype/amount of one or more agents to be administered to the patient atthe wound site. A lower level of protein may be used to identify a lesstraumatic, hence less damaging surgical cutting instrument. The level ofthese proteins may in general be more useful than the level of thecorresponding mRNA because these protein levels may have been induced bydirect effect of surgery rather than by upregulation of the associatedgene. It should also be understood that the listing of Table 3 is notintended to be exhaustive, as other proteins may be increased after thetrauma of surgery.

TABLE 3 Upregulated Proteins No. Acronym Protein 1 CSTB cystatin Bprotein 2 CTNNA1 Isoform 2 of Catenin alpha-1 3 MAN2B1 lysosomalalpha-mannosidase 4 HTRA1 protease serine 11 (IGF binding) 5 S100A12Protein S100-A12 6 TKT transketolase 7 ANPEP Aminopeptidase N 8 PTPRCprotein tyrosine phosphatase, receptor type, C 9 VPS29 Vacuolar proteinsorting-associated protein 29 10 GPNMB glycoprotein NMB 11 PABPC1similar to Polyadenylate-binding protein 1 (Poly(A)-binding protein 1)(PABP 1) 12 ATP6V1B2 V-type proton ATPase subunit B, brain isoform 13SFRS1 splicing factor arginine/serine-rich 1 14 TCIRG1 T-cell, immuneregulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 15 CTSDcathepsin D 16 COL3A1 Isoform 1 of Collagen alpha-1(III) chain 17 FKBP11peptidyl-prolyl cis-trans isomerase FKBP11 18 ITGB2 CD18 19 IDH1Isocitrate dehydrogenase [NADP] cytoplasmic 20 DHX9; DHX9 ATP-dependentRNA helicase A 21 ITGAL integrin alpha-L precursor 22 FLNA Isoform 1 ofFilamin-A 23 ICA; PICA porcine inhibitor of carbonic anhydrase precursor24 SLC25A6 solute carrier family 25 member 6 25 FLNC Filamin-C 26 TLN1talin 1 27 ACTR2 actin-related protein 2-like protein 28 RPL26L1ribosomal protein L26-like 1 29 ATP6V1E1 similar to Vacuolar proton pumpsubunit E 1 (V-ATPase subunit E 1) (V-ATPase 31 kDa subunit) (P31) 30GUCY1B3 soluble guanylate cyclase 1 beta 3 31 MYH14 myosin, heavy chain14 isoform 3 32 GENSCAN000 chromosome:Sscrofa9:6:38101539:38110768:-100034603 transcript:GENSCAN00000034603 33 TNC tenascin C 34 EIF4A1eukaryotic initiation factor 4A-I 35 CLTC clathrin heavy chain 36 ARPC1Bactin related protein 2/3 complex subunit 1B 37 ANXA1 similar to annexin1, partial 38 BGN biglycan 39 VIM vimentin 40 MYH10 myosin, heavy chain10, non-muscle isoform 1 41 CKAP4 Isoform 1 of Cytoskeleton-associatedprotein 4 42 LGALS3 lectin galactoside-binding soluble 3 43 NPG4Antibacterial peptide PMAP-37 44 LRP1 low density lipoproteinreceptor-related protein 1 45 C3 complement component C3 46 GNAI2guanine nucleotide-binding protein G(i) subunit alpha-2 47 P4HA1 prolyl4-hydroxylase subunit alpha-1 48 GENSCAN000chromosome:Sscrofa9:14:110127633:110157746:1 00016869transcript:GENSCAN00000016869 49 LAMP-1 lysosome-associated membraneglycoprotein 1 50 HBA Hemoglobin subunit alpha 51 DES muscle-specificintermediate filament desmin 52 ACTN1 alpha-actinin-1 53 HBB Hemoglobinsubunit beta 54 SCARB2 lysosome membrane protein 2 55 CD48 CD48 antigen56 GRB2 growth factor receptor bound protein 2 57 MYH9 myosin-9 58GLIPR2 Golgi-associated plant pathogenesis-related protein 1 59 CAPZBF-actin capping protein beta subunit 60 CAPN2 calpain 2 61 RPL4 60Sribosomal protein L4 62 RAC2 Ras-related C3 botulinum toxin substrate 263 CRP C-reactive protein 64 PTBP1 polypyrimidine tract-binding protein65 CORO1C similar to Coronin-1C (Coronin-3) (hCRNN4) 66 HNRNPA1heterogeneous nuclear ribonucleoprotein A1 67 SFRS7 Splicing factor,arginine/serine-rich 7 68 CLU complement cytolysis inhibitor 69 ANXA2Annexin A2 70 Rrbp1 similar to ribosome receptor 71 Pzp similar toAlpha-2-macroglobulin precursor (Pregnancy zone protein) (Alpha-2-M) 72GENSCAN000 chromosome:Sscrofa9:2:7434734:7455121:1 00037410transcript:GENSCAN00000037410 73 AP2B1 Isoform 2 of AP-2 complex subunitbeta 74 PLG plasminogen precursor 75 PSME1 proteasome activator 28 alphasubunit 76 COL1A1 Collagen alpha-1(I) chain 77 ASPN asporin precursor 78HNRNPH1 Heterogeneous nuclear ribonucleoprotein H 79 A1BG alpha-1-Bglycoprotein 80 AIMP1 small inducible cytokine subfamily E member 1 81EEF2 Elongation factor 2 82 AP1B1 similar to AP1B1 83 MYL6 myosin lightpolypeptide 6 84 GENSCAN000 chromosome:Sscrofa9:9:116512127:116526965:100035285 transcript:GENSCAN00000035285 85 EEF1A1 eukaryotic translationelongation factor 1 alpha 86 ARPC2 actin related protein 2/3 complexsubunit 2 87 ANXA4 annexin A4 88 FMOD Fibromodulin 89 CLINT1 Clathrininteractor 1 90 S100A10 similar to S100 calcium binding protein A10 91PYCR1 Pyrroline-5-carboxylate reductase 92 APOA1 Apolipoprotein A-I 93CTSB cathepsin B 94 ACTB Actin, cytoplasmic 1 95 HDLBP HDL bindingprotein 96 HNRNPA2B1 Isoform B1 of Heterogeneous nuclearribonucleoproteins A2/B1 97 COX6A1 cytochrome c oxidase subunit VIapolypeptide 1 98 SQRDL sulfide: quinone oxidoreductase, mitochondrial 99HK1 similar to hexokinase 1 100 CAPZA1 F-actin capping protein subunitalpha 1 101 APOH beta-2-glycoprotein 1 precursor 102 PPIB similar topeptidylprolyl isomerase B 103 CAP1 56 kda actin-sequestering protein,ASP-56 = peptide T26/27 104 S100A4 similar to Protein S100-A4 (S100calcium-binding protein A4) (Metastasin) (Protein Mts1) (Placentalcalcium-binding protein) (Calvasculin) isoform 2 105 NAP1L4 Nucleosomeassembly protein 1-like 1 106 VAT1 Synaptic vesicle membrane proteinVAT-1 homolog 107 MSN Moesin 108 HNRNPC Isoform C2 of Heterogeneousnuclear ribonucleoproteins C1/C2 109 SCP2 sterol carrier protein 2 110GENSCAN000 chromosome: Sscrofa9:14:49771686:49783007:1 00042293transcript:GENSCAN00000042293 111 HSP90; heat shock protein HSP 90-alphaHSP90AA1 112 FERMT3 fermitin family homolog 3 113 ITGB3 glycoproteinGPIIIa 114 NUCB1 nucleobindin 1 115 COL6A3 collagen, type VI, alpha 3116 COPB2 Coatomer subunit beta 117 AP2M1 cDNA FLJ53069, highly similarto AP-2 complex subunit mu-1 118 COPG Coatomer subunit gamma 119 LRPAP1alpha-2-macroglobulin receptor-associated protein 120 DYNC1H1Cytoplasmic dynein 1 heavy chain 1 121 CTSC cathepsin C 122 ATP6V1AV-type proton ATPase catalytic subunit A 123 COPA coatomer proteincomplex, subunit alpha isoform 1 124 SERPINB1 similar to Leukocyteelastase inhibitor (LEI) (Serpin B1) (Leukocyte neutral proteinaseinhibitor) (LNPI) 125 AP2A1 Isoform A of AP-2 complex subunit alpha-1126 RPL8 similar to ribosomal protein L8 127 SERPINH1 serpin H1precursor 128 PDIA6 Protein disulfide-isomerase A6 129 GENSCAN000chromosome:Sscrofa9:7:22008598:22010499:-1 00044034transcript:GENSCAN00000044034 130 PDAP1 28 kDa heat- and acid-stablephosphoprotein 131 ARPC3 actin-related protein 2/3 complex subunit 3 132HNRNPK Isoform 2 of Heterogeneous nuclear ribonucleoprotein K 133 PFN1Profilin-1 134 LUM similar to lumican 135 RAB14 Ras-related proteinRab-14 136 COPE Coatomer subunit epsilon 137 GOLIM4 Golgi integralmembrane protein 4 138 COPB1 coatomer protein subunit beta 1 139LOC733658 hypothetical protein 140 ALB albumin 141 RPL7 60S ribosomalprotein L7 142 ARL1 ADP-ribosylation factor-like protein 1 143 HNRNPRHeterogeneous nuclear ribonucleoprotein-R2 144 SERPINA3-3alpha-1-antichymotrypsin 3 145 ITIH1 inter-alpha-trypsin inhibitor heavychain H1 precursor 146 STOM Erythrocyte band 7 integral membrane protein147 ARCN1 Coatomer subunit delta variant 2 148 H1FT Histone H1t 149HNRNPU Isoform Long of Heterogeneous nuclear ribonucleoprotein U 150RPL17 60S ribosomal protein L17 151 GNB2L1 guanine nucleotide-bindingprotein subunit beta-2-like 1 152 PFKL 6-phosphofructokinase, liver type(EC 2.7.1.11) (Phosphofructokinase 1) (Phosphohexokinase)(Phosphofructo-1- kinase isozyme B) (PFK-B). Isoform 2 153 UFTartrate-resistant acid phosphatase type 5 154 S100A8 calcium-bindingprotein Si 00A8 155 GENSCAN000chromosome:Sscrofa9:6:119512835:119582882:-1 00011448transcript:GENSCAN00000011448 156 EIF3F Eukaryotic translationinitiation factor 3 subunit F 157 HMGB2 High mobility group protein B2158 EIF4G1 EIF4G1 protein 159 EIF3I Eukaryotic translation initiationfactor 3 subunit I 160 RPS3A ribosomal protein 53A 161 HBA1 HemoglobinAlpha 1 162 HBA2 Hemoglobin Alpha 2 163 PREP Prolyl endopeptidase 164IGHM Immunoglobulin mu heavy chain constant region 165 HBE1 HemoglobinEpsilon 1 166 TYSND1 Peroxisomal leader peptide-processing protease 167RIC8B Resistance to inhibitors of cholinesterase 8 homolog B 168 KPNA3Karyopherin Alpha-3 (Importin-4) 169 PAPPA Pregnancy-Associated PlasmaProtein A 170 GRK7 G protein-coupled receptor kinase 7 171 RPL7L1 60Sribosomal protein L7-like 1 172 PI4 Protease Inhibitor 4 173 PCI ProteinC Inhibitor 174 SERPINA6 Serpin Peptidase Inhibitor, Clade A, Member 6175 DNAH10 Dynein, Axonemal, Heavy Chain 10 176 CYP26A1 Cytochrome P45026A1 177 APOA4 Apolipoprotein A-IV 178 ABO Histo-blood group ABO systemtransferase 179 MED12 Mediator of RNA polymerase II transcriptionsubunit 12 180 HIST1H4J Histone H4 181 HIST1H2AD Histone H2A type 1-D182 ETFB Electron transfer flavoprotein subunit beta 183 PIK3CGPhosphoinositide-3-kinase, catalytic, gamma polypeptide 184 GPX8Glutathione peroxidase 8 185 MYO1D Myosin-1d

Table 4 provides a listing of proteins that are decreased after thetrauma of surgery. These proteins may be used to determine the degree oftrauma resulting from the use of a particular medical device when makingan incision. A decrease in the level of the protein indicates greatertissue damage from the medical device. A smaller decrease in the levelof the protein can therefore be used to identify a less traumatic, henceless damaging surgical cutting instrument. In addition or in thealternative, a smaller decrease in the level of the protein may be usedto identify a reduced susceptibility of a particular patient to tissuedamage; and such information may thus be used to modify the selection ofa medical device for use on the patient, to modify the way in which amedical device is used in/on the patient, and/or to select thetype/amount of one or more agents to be administered to the patient atthe wound site. The level of these proteins may in general be moreuseful than the level of the corresponding mRNA because these proteinlevels may have been directly affected by surgery rather than byupregulation of the associated gene. It should also be understood thatthe listing of Table 4 is not intended to be exhaustive, as otherproteins may be decreased after the trauma of surgery.

TABLE 4 Downregulated Proteins No. Acronym Protein 1 FASN Fatty AcidSynthase 2 FABP4 Fatty Acid Binding Protein 4 3 HLA-DQB1 MajorHistocompatibility Complex, Class II, Dq Beta-1 4 TF Transferrin 5 ADAM7A Disintegrin And Metalloproteinase Domain 7 6 BTBD9 BTB/POZDomain-Containing Protein 9 7 F9 Coagulation Factor IX 8 HPX Hemopexin 9BTBD1 BTB/POZ Domain-Containing Protein 1 10 EML5 Echinodermmicrotubule-associated protein-like 5 11 AACT Alpha-1-Antichymotrypsin12 PLN Perilipin 13 TOP2A DNA Topoisomerase 2 14 COL6A2 Alpha 2 Type VICollagen 15 CHDH Choline dehydrogenase, mitochondrial 16 GSN Gelsolin 17TUBB Tubulin beta polypeptide 18 ANKRD60 Ankyrin Repeat Domain 60 19BMP1 Bone Morphogenetic Protein 1 20 PS1TP5BP1 PS1TP5-binding protein 121 VDAC1P5 voltage-dependent anion-selective channel protein 3 22 UQCRC1similar to ubiquinol--cytochrome c reductase 23 UQCRQ cytochrome b-c1complex subunit 8 24 ATP5B mitochondrial ATP synthase, H+ transportingF1 complex beta subunit 25 ATP2A1 sarcoplasmic/endoplasmic reticulumcalcium ATPase 1 26 EPM2A similar to Laforin (Lafora PTPase) (LAFPTPase)27 ATP2A2; Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 SERCA2 28GENSCAN000 chromosome:Sscrofa9:13:76148115:76308481:1 00038257transcript:GENSCAN00000038257 29 NIPSNAP3A similar to Protein NipSnaphomolog 3A (NipSnap3A) (NipSnap4) (Target for Salmonella secretedprotein C) (TassC) 30 DHRS7C dehydrogenase/reductase (SDR family) member7C 31 FH Fumarate hydratase, mitochondrial 32 MACROD1 MACRO domaincontaining 1 33 HIBADH 3-hydroxyisobutyrate dehydrogenase 34 OGDH OGDHprotein 35 TRDN Triadin 36 HECW1 E3 ubiquitin-protein ligase HECW1 37Srl sarcalumenin 38 Casq1 similar to calsequestrin skeletal muscle 39CACNB1 Isoform 2 of Voltage-dependent L-type calcium channel subunitbeta-1 40 GENSCAN000 chromosome:Sscrofa9:6:32691305:32779467:-1 00042606transcript:GENSCAN00000042606 41 RYR1 ryanodine receptor 42 PYGM muscleglycogen phosphorylase 43 CAMK2A calcium/calmodulin-dependent proteinkinase II alpha isoform 1 44 Phkg1 phosphorylase kinase, gamma 1 45 PYGBGlycogen phosphorylase, brain form 46 HRC sarcoplasmic reticulumhistidine-rich calcium-binding protein 47 AMPD1 adenosine monophosphatedeaminase 1 48 IDH3B mitochondrial NAD + isocitrate dehydrogenase 3 betavariant 1 49 LCTHIO long-chain 3-ketoacyl-CoA thiolase 50 RTN4reticulon-4 51 AGL amylo-1,6-glucosidase,4-alpha-glucanotransferase-like 52 MDH2 Malate dehydrogenase,mitochondrial 53 CACNA1S; Voltage-dependent L-type calcium channelsubunit alpha-1S CACNA1S 54 CAMK2G calcium/calmodulin-dependent proteinkinase type II subunit gamma 55 STBD1 similar to Starch-bindingdomain-containing protein 1 (Genethonin- 1) 56 COX7A1 cytochrome coxidase polypeptide VIIa-muscle/heart 57 ACO2 Aconitate hydratase,mitochondrial 58 MURC similar to PTRF/SDPR family protein 59 PFMK muscle6-phosphofructokinase 60 CKMT2 creatine kinase S-type, mitochondrial 61SLC25A4 Solute carrier family 25 member 4 variant (Fragment) 62 GYS1Glycogen [starch] synthase, muscle 63 IDH2 isocitrate dehydrogenase[NADP], mitochondrial 64 DLD Dihydrolipoyl dehydrogenase 65 NDUFS6 NADHdehydrogenase (ubiquinone) Fe-S protein 6, 13 kDa (NADH- coenzyme Qreductase) 66 PHKB Phosphorylase b kinase regulatory subunit beta 67CRAT camitine acetyl transferase 68 CPSF2 similar to cleavage andpolyadenylation specific factor 2, 100 kDa 69 NDUFS3 NADH dehydrogenase(ubiquinone) Fe-S protein 3, 30 kDa (NADH- coenzyme Q reductase) 70NDUFA7 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 71 COX6BCOX6B 72 ATP5L ATP synthase subunit g, mitochondrial 73 SDHA Succinatedehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial 74 COQ10Asimilar to coenzyme Q10 homolog A 75 NDUFB9 similar to NADHdehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 (NADH-ubiquinoneoxidoreductase B22 subunit) (Complex I-B22) (CI-B22) 76 NDUFA12 NADHdehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12

It will be understood by one skilled in the art that not only thespecific gene or protein listed can be useful in identifying lessdamaging surgical instruments, but that other members of the proteinfamily, which includes the specific gene or protein, may also be used.For example, both Alpha 3 type VI collagen and Alpha 2 type VI collagenmay be decreased after surgical intervention. Other isoforms or familymembers of collagen could likewise be used as biomarkers of traumainduced by surgery. Assays may involve either a specific member of afamily of genes or proteins, or may include a partial or completecombination of the genes or proteins of a family.

Table 5 provides a listing of proteins that are believed to bebeneficial to the long-term healing process. These proteins may thus beused to determine the speed of healing from a wound, such as a woundcaused by a medical device. In particular, a surgical device thatincreases the level of these proteins should provide a relatively morerapid wound healing (as compared to a surgical device that fails toincrease the protein levels or does not increase the protein levels asmuch). In addition or in the alternative, these proteins may be used todetermine a particular patient's propensity to heal, such that increasedlevels of these proteins may demonstrate a relatively greater propensityof the particular patient to heal from tissue trauma. It should also beunderstood that the listing of Table 5 is not intended to be exhaustive,as other proteins may be beneficial to the long-term healing process.

TABLE 5 Beneficial Upregulated Proteins No. Acronym Protein 1 MYO1DMyosin-Id 2 ATL3 Isoform 1 of Atlastin-3 3 GUSB beta-glucuronidaseprecursor 4 NAGA N-acetylgalactosaminidase alpha 5 S100A6 proteinS100-A6 6 LDHA L-lactate dehydrogenase A chain 7 MYOF PREDICTED:fer-1-like 3, myoferlin (C. elegans) 8 FCGR3B Low affinityimmunoglobulin gamma Fc region receptor III 9 MYOF Isoform 1 ofMyoferlin 10 SBAB- major histocompatibility complex, class II, DR beta 1591C4.1; SLA- DRB1 11 NT5E similar to 5 nucleotidase, ecto 12 Dync1h1cytoplasmic dynein 1 heavy chain 1 13 Ap2a2 adaptor-related proteincomplex 2, alpha 2 subunit 14 ANXA5 annexin AS 15 PDIA5 proteindisulfide-isomerase AS 16 AHNAK Neuroblast differentiation-associatedprotein AHNAK 17 IQGAP1 Ras GTPase-activating-like protein IQGAP1 18RPL38 60S ribosomal protein L38 19 TUBB2A tubulin beta chain 20 BEST3bestrophin 3 21 TUBB1 Tubulin beta-1 chain 22 AP2S1 Isoform 1 of AP-2complex subunit sigma 23 PTGIS Prostaglandin I2 (prostacyclin) synthase24 CNN2 h2-calponin 25 TXNDC5 similar to Thioredoxin domain-containingprotein 5 precursor (Thioredoxin-like protein p46) (Endoplasmicreticulum protein ERp46) 26 RPL9 60S ribosomal protein L9

Table 6 also provides a listing of proteins that are believed to relateto the long-term healing process. These proteins may thus be used todetermine the speed of healing from a wound, such as a wound caused by amedical device. In particular, a surgical device that decreases thelevel of these proteins should provide a relatively more rapid woundhealing (as compared to a surgical device that fails to decrease theprotein levels or does not decrease the protein levels as much). Inaddition or in the alternative, these proteins may be used to determinea particular patient's propensity to heal, such that decreased levels ofthese proteins may demonstrate a relatively greater propensity of theparticular patient to heal from tissue trauma. It should also beunderstood that the listing of Table 6 is not intended to be exhaustive,as other proteins may relate to the long-term healing process.

TABLE 6 Beneficial Downregulated Proteins No. Acronym Protein 1 Uqcrc2ubiquinol cytochrome c reductase core protein 2 2 KRT10 Keratin, type Icytoskeletal 10

Table 7 provides a listing of proteins that respond rapidly to surgicalincisions, and are thus believed to indicate quality or speed ofhemostatis. These proteins may thus be used to determine the superiorityof hemostasis in response to a wound, such as a wound caused by amedical device. In particular, a surgical device that increases thelevel of these proteins should provide relatively better or fasterhemostasis (as compared to a surgical device that fails to increase theprotein levels or does not increase the protein levels as much). Inaddition or in the alternative, these proteins may be used to determinea particular patient's propensity to achieve hemostasis, such thatincreased levels of these proteins may demonstrate a relatively greaterpropensity of the particular patient to achieve hemostasis in responseto tissue trauma. It should also be understood that the listing of Table7 is not intended to be exhaustive, as other proteins may relate to thequality or speed of hemostasis.

TABLE 7 Upregulated Fast-response Proteins No. Acronym Protein 1 EIF3AEukaryotic translation initiation factor 3 subunit A 2 TPM2 Tropomyosin2 3 DARS Aspartyl-tRNA synthetase, cytoplasmic 4 RCN1 Reticulocalbin-1 5PPP1CB protein phosphatase 1 catalytic subunit beta isoform 6 LRRC59Leucine-rich repeat-containing protein 59 7 EEF1G eukaryotic elongationfactor 1 gamma-like protein 8 SEC24C SEC24 related gene family, member C(S. cerevisiae) 9 EIF2S3 Eukaryotic translation initiation factor 2subunit 3 10 HSP70.2 heat shock 70 kDa protein 1A 11 PSMD7 26Sproteasome non-ATPase regulatory subunit 7 12 GLRX5 PRO1238 13 NPG4 PR-2protein 14 HBA Hemoglobin subunit alpha

Table 8 also provides a listing of proteins that respond rapidly tosurgical incisions, and are thus believed to indicate quality or speedof hemostatis. These proteins may thus be used to determine thesuperiority of hemostasis in response to a wound, such as a wound causedby a medical device. In particular, a surgical device that decreases thelevel of these proteins should provide relatively better or fasterhemostasis (as compared to a surgical device that fails to decrease theprotein levels or does not decrease the protein levels as much). Inaddition or in the alternative, these proteins may be used to determinea particular patient's propensity to achieve hemostasis, such thatdecreased levels of these proteins may demonstrate a relatively greaterpropensity of the particular patient to achieve hemostasis in responseto tissue trauma. It should also be understood that the listing of Table8 is not intended to be exhaustive, as other proteins may relate to thequality or speed of hemostasis.

TABLE 8 Downregulated Fast-response Proteins No. Acronym Protein 1SYNCRIP similar to SYNCRIP protein 2 GENSCAN000chromosome:Sscrofa9:12:16859819:16873906:-1 00012699transcript:GENSCAN00000012699 3 EPB42 erythrocyte membrane protein band4.2

III. Exemplary Uses of Biomarkers to Influence Use of Therapeutic Agents

In addition to assessing the effectiveness of surgical devices,biomarkers as described herein may also be used to assess thecombination of the most desirable surgical device along with one or moretherapeutic agents (or even just the most desirable therapeuticagent(s), without also determining the most desirable surgical device).Hence, concepts described herein could be used to develop a combinationof a surgical device and/or one or more therapeutic agents that reducethe trauma of surgery by monitoring the levels or production ofbiomarkers identified in real-time during the course of the surgery.Such methods could be especially useful in chronic wounds or burns wheremultiple surgical debridement of dead tissue is needed throughout aprolonged recovery phase; or in any wound where the measurement ofspecific biomarkers would aid in the determination of the course oftreatment. Additionally, matrix metalloproteinase may delay woundhealing where burn studies in muscle show down-regulation ofmitochondrial oxidative phosphorylation and related functions.

An example of a type of therapeutic agent that may reduce the trauma ofsurgery is vasoconstrictors. Vasoconstrictors, including a-adrenergicsympathomimetics, act by constricting blood vessels and hence bloodflow. Since surgery can result in blood loss when veins, arteries orcapillaries are breached, use of vasoconstrictors can be beneficial inreducing or preventing unintentional blood loss. By reducing blood loss,the amount of tissue trauma is also decreased, and this will be evidentin a modulation of the biomarkers identified in this technology. Theefficacy of the combination of surgical device with one or morevasoconstrictors may thus be assessed by monitoring the biomarkers.Although visual observation of bleeding during surgery provides someestimate of the efficacy of the vasoconstrictor, the biomarkersidentified can be more beneficially used to evaluate cumulative traumainduced after the wound is closed and the incision site is no longervisible and/or when visual observation is not adequate. Examples ofvasoconstrictors include, but are not limited to, amidephrine,cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypressin,indanazoline, metizoline, midodrine, naphazoline, nordefrin, octodrine,ornipressin, oxymetazoline, phenylephrine, phenylethanolamine,phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline,tramazoline, tuaminoheptane, tymazoline, vasopressin, xylometazoline andmixtures thereof.

Another example of a type of therapeutic agent that may reduce thetrauma of surgery is corticosteroids. Corticosteroids suppress theimmune system. When surgery induces tissue trauma, a severeover-reaction of the immune system can occur. By suppressing theover-reaction of the immune system, the amount of tissue trauma may alsobe decreased, and this may be evident in a modulation of the relevantbiomarkers. The efficacy of the combination of surgical device with oneor more corticosteroids may thus be assessed by monitoring thebiomarkers. Examples of corticosteroids include, but are not limited to,hydrocortisone, cortisone, prednisolone, prednisone, dexamethasone,betamethasone, triamcinolone, fluocinolone, methylprednisolone,fluorometholone, or an ester thereof when chemically possible.

Another example of a type of therapeutic agent that may reduce thetrauma of surgery is non-steroidal anti-inflammatory drugs (NSAIDs).NSAIDs reduce inflammation and accompanying pain. When surgery inducestissue trauma, an inflammatory response and accompanying pain may occur.By suppressing the inflammatory response, the amount of tissue traumamay also be decreased, and this may be evident in a modulation of thebiomarkers identified. The efficacy of the combination of surgicaldevice with one or more NSAIDs may thus be evaluated by monitoring thebiomarkers. Examples of NSAIDs include, but are not limited to,salicylic acid, acetylsalicylic acid (aspirin), bis-salicylate,benzyl-benzoic acid, diflunisal, fendosal, indomethacin, acemetacin,cinmetacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac,isoxepac, ibuprofen, flurbiprofen, naproxen, ketoprofen, fenoprofen,benoxaprofen, indoprofen, pirprofen, carprofen, mefenamic acid,flufenamic acid, meclofenamate, niflumic acid, tolfenamic acid,flunixin, clonixin, phenylbutazone, feprazone, apazone, trimethazone,mofebutazone, kebuzone, suxibuzone, piroxicam, isoxicam and tenoxicam.

Another example of a therapeutic agent that may reduce the trauma ofsurgery is DNA. By inserting DNA into the cells at the site of thesurgery, the DNA may express proteins that are beneficial in reducingsurgical trauma and hasten wound healing. The inserted genes may codefor any number of different proteins necessary to facilitate tissuerecovery. Those proteins that may have a beneficial effect include, butare not limited to, transforming growth factor beta (TGF-β). TGF-β playsa key role in the proliferation and migration of fibroblasts which arean essential part of the wound healing process. By combining theinsertion of the DNA for TGF-β into cells at the surgery site with thesurgery itself, the wound healing process may be hastened, and this canbe monitored by measuring the biomarkers identified.

Various methods may be used to effect insertion of DNA into cells, suchas attachment of the DNA to a viral carrier, such as an adenovirus.Another method is to use electrical or mechanical poration of the cellmembrane. Accordingly, in some versions, a combination of a surgicaldevice and a separate device for DNA insertion may be used.Alternatively, the same device may be used for both the surgery and theDNA insertion. An example of a single device that would accomplish boththe surgery and DNA insertion would be a surgical device energized byultrasonics in which the ultrasonic energy both mechanically cuts tissueand also induces cell poration for insertion of DNA into cells. Thebiomarkers identified could then be used to evaluate the degree oftissue trauma and state of the wound healing process, and hence theefficacy of the combination of surgical device and gene therapy-basedtreatments. Various examples of how genes may be inserted into the cellsat the site of the surgery will be described in greater detail below(e.g., section V.D., below), while other examples will be apparent tothose of ordinary skill in the art in view of the teachings herein.

As described herein, therapeutic agents, etc. may be administered to apatient in response to biomarker data before, during, and/or after asurgical procedure. For instance, it should be understood that a givenpatient's biological response (e.g., particular sensitivities and/orpropensities for pain/bleeding/healing/revascularization, etc.) to awound (e.g., traumatic wound or iatrogenic wound, etc.) may differ fromthe biological response of another patient to the same kind of wound.Such variance in wound response may be based on the particular patient'sgenetic makeup, prior history, and/or other factors. Thus, it may beuseful in some settings to anticipate a particular patient's biologicalresponse to a wound before the patient undergoes a surgical procedure.With such information, the patient may be provided certain therapies(e.g., agents) before, during, and/or after the surgery to address theanticipated wound response. In addition or in the alternative, thesurgery itself may be tailored based on the anticipated wound responsefor that particular patient, such as by selection of surgical technique,selection of surgical instruments, selection of operating parameters forsurgical instruments, etc. Being able to anticipate a particularpatient's unique biological response to a wound may thus be used tooptimally customize treatment for that particular patient.

By way of example only, if it is discovered before surgery that thepatient has a weak propensity to clot (e.g., as evidenced by a lack ofclotting factors), this may be compensated for by administration ofclotting factors before a surgical procedure is performed in a highlyvascularized organ. As another merely illustrative example, if it isdiscovered through biomarker data before surgery that the patient has anexcessive response to thermal injury, a surgeon may elect to usecryoablation or a Harmonic scalpel instead of using thermal ablation orelectrocautery. An excessive inflammatory response could be anticipatedand countered before and after the procedure with antihistamines. As yetanother merely illustrative example, a patient who will be undergoingmajor surgery may have a pre-surgery microwound made with anelectrosurgical tool in the subcutaneous tissue of the upper arm. Abiopsy may later be performed at the site (e.g., 48 hours after themicrowound is inflicted) and the sample may be assayed for arginase viaimmunoassay. If the level is higher than normal, the subject may begiven supplemental arginine prior to the surgery. Other examples ofresponses to biomarker data will be apparent to those of ordinary skillin the art in view of the teachings herein.

In order to anticipate a particular patient's biological response to awound before the patient undergoes a surgical procedure, the patient maybe inflicted with a relatively trivial (i.e., small, minimallyaffective) “test wound” such as a scratch, burn, puncture, etc., at sometime before the surgical procedure is to begin. The patient's biologicalresponse (e.g., local or systemic, immunologic, protein or genomicexpression changes, etc.) to that “test wound” may be measured based onbiomarkers as described herein. The response may be measured within anysuitable time frame(s) and for any suitable duration(s). In somesettings, and if measurements can be performed rapidly enough, similarconclusions about the particular patient's biological response to awound may be drawn and utilized to optimize a surgical procedure as thesurgical procedure is being performed, such that no pre-surgical “testwound” is needed.

Continuing with the example of anticipating a particular patient'sbiological response to a wound, it should be understood that periodicre-exposure and evaluation might be warranted in some situations (e.g.,since a person's acquired immunologic response may change with time),such that any emergency therapy may be optimized just as aplanned/elective therapy could be optimized. It should also beunderstood that, in some instances, cells may be cultured in vitro as aless traumatic method of biomarker sampling that eliminates the need fora “test wound.”

As noted previously, some biomarkers may be expressed immediately,others within hours, others within a week, others within several weeks,etc.; and it may therefore be useful in some instances to tailorbiomarker monitoring based on timing, such as to only look for certainbiomarkers during certain time frames. For instance, some biomarkerssuch as those associated with inflammatory and immune response may beexpressed about two to seven days after a wound is inflicted (or theexpression of such biomarkers may otherwise change around that timeperiod). With respect to therapies or other selections that may be made,it may be desirable to take steps to reduce those biomarkers that areassociated with inflammatory and immune response. As another example,some biomarkers such as those associated with angionenesis and myofiberremodeling may be expressed about three weeks after a wound is inflicted(or the expression of such biomarkers may otherwise change around thattime period). With respect to therapies or other selections that may bemade, it may be desirable to take steps to augment those biomarkers thatare associated with remodeling. Thus, the ability to identify the propertherapeutic response to certain biomarker expressions, and to monitorthe efficacy of therapeutic responses to certain biomarker expressions,may be tied to particular time frames following the infliction of awound (be it a “test wound” or a true surgical wound, etc.).

Various other examples of ways in which therapeutic agents, etc. may beadministered in response to biomarker data will be described in greaterdetail below (e.g., section V.B. and section V. D., below), while otherexamples will be apparent to those of ordinary skill in the art in viewof the teachings herein. It should also be understood that various othertypes of adjustments may be made in response to biomarker data inaddition to or in lieu of administration of therapeutic agents, etc.,including but not limited to selection of surgical technique, selectionof surgical instruments, selection of operating parameters for surgicalinstruments, etc. Various other types ofactions/selections/adjustments/etc. that may be made in response tobiomarker data will be apparent to those of ordinary skill in the art inview of the teachings herein.

IV. Exemplary Use of Biomarkers to Evaluate Trauma Caused by CuttingInstruments

The following examples relate to various illustrative ways in whichbiomarkers may be used to evaluate trauma caused by cutting instruments.These examples are provided as experiments described with verbs writtenin the present tense, though it should be understood that various otherkinds of experiments/processes may be carried out to demonstrate theteachings herein.

EXAMPLE No. 1 Use of UPregulated Genes to Evaluate Surgical Instruments

Four equally-spaced midline, 4 cm length, caudal abdominal incisions arecreated in two pigs. The umbilical scar region is avoided. An ultrasonicscalpel (Harmonic Blade HK105, by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio) is used for two incisions and conventional monopolarelectrosurgery is used for two incisions on each animal. Using a skinmarker, the incision sites are marked on the ventral aspect of theabdomen and identified by level from cranial to caudal, as incision A,B, C, and D respectively. The incision is started with a scalpel bladethrough the skin (epidermis and dermis). Each incision is deepenedthrough the subcutaneous tissues down to the linea alba. The HarmonicBlade HK105 is set at Power level 5 for cutting tissue and Power level 3for coagulating bleeders. Monopolar electrosurgery is set at 40 Wattscutting and 40 Watts coagulation with Blend 2/Spray coagulation.Electrosurgery is used in the cutting mode with the coagulation Blend2/Spray to coagulate bleeders. The linea alba is not incised.

Closure of the incision is effected by apposing the skin with 3-0 nylonin a simple interrupted pattern. Dermabond is applied to seal theepidermis. No bandages are applied to the incisions.

After three days, the pigs are euthanized and each incision site isremoved enbloc from the abdominal wall. The tissue block is slicedperpendicular to the surgical incision to create slabs about 4-6 mmthick. The slab is trimmed to remove the skin from the top and musclefrom the bottom of the sample. The side walls are trimmed toapproximately 4 mm from the surgical incision leaving a rectangularblock of subcutaneous fatty tissue. Four to six samples are taken fromeach incision site and from a control site, which had not previouslybeen incised. Samples are placed in sterile DNAse-, RNAse-, protein-freeEppendorf tubes, flash frozen in liquid nitrogen (LN₂), and then held ondry ice throughout tissue collection. The samples are stored in a −80°C. freezer.

Total RNA is isolated in quadruplicate from 100 mg of tissue (four eachof control, electrosurgery, and Harmonic). The frozen tissue samples arepulverized in liquid nitrogen and Qiazol buffer (Qiagen; 500 μL persample) and then further homogenized using Qiashredder columns (Qiagen).RNA is purified using the RNase-Free DNase Set and the RNeasy LipidTissue Mini Kit (Qiagen). Isolated RNA is quantifiedspectrophotometrically (NanoDrop™ 1000; Thermo Scientific) and RNAquality measured (2100 Bioanalyzer and RNA 6000 Nano chips, AgilentTechnologies). Only RNA with high integrity (RIN>8.0; 28S/18S>2.0) andconcentration (>800 ng/μL) are used in microarray experiments and RNAsamples are repurified until each exceeded these standards. Purified RNAis labeled using the One-Cycle Eukaryotic Target Labeling Assay(Affymetrix). Labeled RNA is hybridized to the GeneChip Porcine GenomeArrays (Affymetrix) which contain 23,937 probe sets to interrogate23,256 transcripts in pig. The arrays are scanned at the FluidicsStation 400 (Affymetrix) and microarray expression data are generatedwith GeneChip Operating Software (GCOS; Affymetrix). Log transformed rawintensity values for all chips are normalized using RMA Express 1.0.4(Bolstad et al. Bioinformatics 19:185-193), using Background Adjust,Quantile Normalization, PLM (Probe Level Method). Differential mRNAexpression analysis is performed using t-tests. Annotations are takenfrom S. Tsai et al. Animal Genetics 37 423 (2006).

The measured fold-change for upregulation of mRNA expression for severalgenes of the test devices relative to the control device is given in thefollowing table 5.

TABLE 5 Harmonic/Control Upregulated Genes Electrosurgery/Control Fold-Acronym Gene Name Fold-Change p-value Change p-value CXCL6 Granulocyte122.8 <0.001 77.3 p < 0.001 chemotactic protein 2 CXCL8 Interleukin-8111.2 <0.001 17.3 <0.001 ARG1 Arginase-1 86.3 <0.001 25.6 <0.001

The fold-changes for Electrosurgery vs. Control are all higher than thefold-changes for Harmonic vs. Control. This quantitative result is inagreement with qualitative observations made over a much longer durationthat the Harmonic device produces less tissue trauma and better woundhealing than Electrosurgery. Hence these biomarkers are useful for fast,quantitative assessment of the quality of the surgical device.

EXAMPLE No. 2 Use of Down-Regulated Genes to Evaluate SurgicalInstruments

Four equally-spaced midline, 4 cm length, caudal abdominal incisions arecreated in two pigs. The umbilical scar region is avoided. An ultrasonicscalpel (Harmonic Blade HK105, by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio) is used for two incisions and conventional monopolarelectrosurgery is used for two incisions on each animal. Using a skinmarker, the incision sites are marked on the ventral aspect of theabdomen and identified by level from cranial to caudal, as incision A,B, C, and D respectively. The incision is started with a scalpel bladethrough the skin (epidermis and dermis). Each incision is deepenedthrough the subcutaneous tissues down to the linea alba. The HarmonicBlade HK105 is set at Power level 5 for cutting tissue and Power level 3for coagulating bleeders. Monopolar electrosurgery is set at 40 Wattscutting and 40 Watts coagulation with Blend 2/Spray coagulation.Electrosurgery is used in the cutting mode with the coagulation Blend2/Spray to coagulate bleeders. The linea alba is not incised.

Closure of the incision is effected by apposing the skin with 3-0 nylonin a simple interrupted pattern. Dermabond is applied to seal theepidermis. No bandages are applied to the incisions.

After three days, the pigs are euthanized and each incision site isremoved enbloc from the abdominal wall. The tissue block is slicedperpendicular to the surgical incision to create slabs about 4-6 mmthick. The slab is trimmed to remove the skin from the top and musclefrom the bottom of the sample. The side walls are trimmed toapproximately 4 mm from the surgical incision leaving a rectangularblock of subcutaneous fatty tissue. Four to six samples are taken fromeach incision site and from a control site, which had not previouslybeen incised. Samples are placed in sterile DNAse-, RNAse-, protein-freeEppendorf tubes, flash frozen in liquid nitrogen (LN₂), and then held ondry ice throughout tissue collection. The samples are stored in a −80°C. freezer.

Total RNA is isolated in quadruplicate from 100 mg of tissue (four eachof control, electrosurgery, and Harmonic). The frozen tissue samples arepulverized in liquid nitrogen and Qiazol buffer (Qiagen; 500 μL persample) a homogenized using Qiashredder columns (Qiagen). RNA ispurified using the RNase-Free DNase Set and the RNeasy Lipid Tissue MiniKit (Qiagen). Isolated RNA is quantified spectrophotometrically(NanoDrop™ 1000; Thermo Scientific) and RNA quality measured (2100Bioanalyzer and RNA 6000 Nano chips, Agilent Technologies). Only RNAwith high integrity (RIN>8.0; 28S/18S>2.0) and concentration (>800ng/μL) a

exceeded these standards. Purified RNA is labeled using the One-CycleEukaryotic Target Labeling Assay (Affymetrix). Labeled RNA is hybridizedto the GeneChip Porcine Genome Arrays (Affymetrix) which contain 23,937probe sets to interrogate 23,256 transcripts in pig. The arrays arescanned at the Fluidics Station 400 (Affymetrix) and microarrayexpression data are generated with GeneChip Operating Software (GCOS;Affymetrix). Log transformed raw intensity values for all chips arenormalized using RMA Express 1.0.4 (Bolstad et al. Bioinformatics19:185-193), using Background Adjust, Quantile Normalization, PLM (ProbeLevel Method). Differential mRNA expression analysis is performed usingt-tests. Annotations are taken from S. Tsai et al. Animal Genetics 37423 (2006).

The measured fold-change for downregulation of mRNA expression forseveral genes of the test devices relative to the control device isgiven in the following table 6.

TABLE 6 Control/Harmonic Downregulated Genes Control/ElectrosurgeryFold- Acronym Gene Name Fold-Change p-value Change p-value PON3Paraoxonase 3 36.0 <0.001 17.6 0.018 MYOC Myocilin 26.3 <0.001 9.6<0.001 AGT Angiotensin 21.2 <0.001 4.5 0.025

The fold-changes for Control vs. Electrosurgery are all greater than thefold-changes for Control vs. Harmonic. This quantitative result is inagreement with qualitative observations made over a much longer durationthat the Harmonic device produces less tissue trauma and better woundhealing than Electrosurgery. Hence these biomarkers are useful for fast,quantitative assessment of the quality of the surgical device.

EXAMPLE No. 3 Use of Elevated Protein Levels to Evaluate SurgicalInstruments

Four equally-spaced midline, 4 cm length, caudal abdominal incisions arecreated in two pigs. The umbilical scar region is avoided. An ultrasonicscalpel (Harmonic Blade HK105, by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio) is used for two incisions and conventional monopolarelectrosurgery is used for two incisions on each animal. Using a skinmarker, the incision sites are marked on the ventral aspect of theabdomen and identified by level from cranial to caudal, as incision A,B, C, and D respectively. The incision is started with a scalpel bladethrough the skin (epidermis and dermis). Each incision is deepenedthrough the subcutaneous tissues down to the linea alba. The HarmonicBlade HK105 is set at Power level 5 for cutting tissue and Power level 3for coagulating bleeders. Monopolar electrosurgery is set at 40 Wattscutting and 40 Watts coagulation with Blend 2/Spray coagulation.Electrosurgery is used in the cutting mode with the coagulation Blend2/Spray to coagulate bleeders. The linea alba is not incised.

Closure of the incision is effected by apposing the skin with 3-0 nylonin a simple interrupted pattern. Dermabond is applied to seal theepidermis. No bandages are applied to the incisions.

After three days, the pigs are euthanized and each incision site isremoved enbloc from the abdominal wall. The tissue block is slicedperpendicular to the surgical incision to create slabs about 4-6 mmthick. The slab is trimmed to remove the skin from the top and musclefrom the bottom of the sample. The side walls are trimmed toapproximately 4 mm from the surgical incision leaving a rectangularblock of subcutaneous fatty tissue. Four to six samples are taken fromeach incision site and from a control site, which had not previouslybeen incised. Samples are placed in sterile DNAse-, RNAse-,(protein-free) Eppendorf tubes, flash frozen in liquid nitrogen (LN₂),and then held on dry ice throughout tissue collection. The samples arestored in a −80° C. freezer.

Total protein is isolated in quadruplicate from tissue (four each ofcontrol, electrosurgery, and Harmonic). The samples are weighed andweights are normalized relative to that of the smallest sample. Samplesare ground in liquid nitrogen in a mortar and pestle and collected innew tubes. Proteins are extracted from the samples using a differentialdetergent fractionation (DDF) procedure. This provides four proteinfractions (cytosolic, membrane/organelle, nuclear and least soluble) foreach sample to give a total of 48 samples to be analyzed by nano-spray2-dimensional liquid chromatography tandem mass spectrometry (2-D LCMS2). Each DDF is then precipitated in 50% trichloroacetic acid (½volume, 30 min) and washed twice in ice-cold acetone (ACN) to removesalts and detergents. Protein pellets are resuspended in 100 mM ammoniumbicarbonate, 5% HPLC grade acetonitrile, reduced (5 mM dithiothreitol,65 C, 10 min), alkylated (10 mM iodoacetamide, 37 C, 30 min) anddigested to complete dissolution with trypsin (1:50 w/w, 37 C, 36 hrs).

The tryptic digests are then centrifuged (13,000 g) and supernatantsspin-filtered (0.45 μm filter; Ultrafree MC, Millipore). Theflow-through is dried out in vacuum centrifuge and resuspended in 250 μlof 2% ACN, 0.1% FA. The samples are further desalted using the PeptideMacro Trap TR1/25108/52 (Michrom Bioresources). Eluted peptides aredried again, and dissolved in 22 μl of 5% ACN and 0.1% formic acid.Twenty microliters of the filtrated peptide mixtures are subjected to2-D LC MS2. The reverse-phase column (BioBasic C18, 0.18×100-mm ThermoHypersil-Keystone) is coupled directly in-line with the electro-sprayionization ion trap mass spectrometer equipped with nano-spray sourceand a column flow rate of 500 nl/min used. The peptides are eluted froma RP column by acetonitrile gradient (in 0.1% FA) of 5%-50% for 580 min,95% for 20 min, 5% for 25 min, a total of 625 min elution. The massspectrometer is configured to collect the spectral data by alternatingbetween a single full MS scan followed by three MS-MS scans on the threemost intense precursor masses from the full MS scan. The collisionenergy is normalized to 35%, the dynamic mass exclusion windows are 2minutes long. MS spectra are measured with an overall mass/charge (m/z)range of 300 to 1,700.

The database of all known porcine genes and human orthogs is used forsearching mass spectra using TurboSEQUEST Cluster v. 3.3 SR1.Isotope-free quantitative analysis is performed and is based on spectralcounting combined with the increased specificity given by including thequantitative aspects of the Sequest cross correlation (XCorr). Decoydatabase searching is used to calculate the probability that a tandemmass spectrometry match occurred by chance and, from these, theprobability of the protein identification occurring by chance. Onlypeptides that are identified at p≦0.05 are used for proteinidentifications. Monte Carlo resampling protein expression analysis isused in conjunction with multiple testing corrections via theBenjamini-Hochberg method.

The measured levels of elevated proteins as given by the sum of thecross correlation is given for Electrosurgery, Harmonic, and Control inthe following table 7.

TABLE 7 Elevated Proteins Sum of Cross Correlation Acronym Gene NameElectrosurgery Harmonic Control HBB Hemoglobin beta 4916.3 1575.7 314.2HBA Hemoglobin alpha 4775.4 3138.0 796.3 PREP Prolyl endopeptidase1003.3 706.7 83.9

The protein levels are compared to Control and are all higher forElectrosurgery cases than for Harmonic cases. This quantitative resultis in agreement with qualitative observations made over a much longerduration that the Harmonic device produces less tissue trauma and betterwound healing than Electrosurgery. Hence these biomarkers are useful forquantitative assessment of the quality of the surgical device.

EXAMPLE No. 4 Use of Decreased Protein Levels to Evaluate SurgicalInstruments

Four equally-spaced midline, 4 cm length, caudal abdominal incisions arecreated in two pigs. The umbilical scar region is avoided. An ultrasonicscalpel (Harmonic Blade HK105, by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio) is used for two incisions and conventional monopolarelectrosurgery is used for two incisions on each animal. Using a skinmarker, the incision sites are marked on the ventral aspect of theabdomen and identified by level from cranial to caudal, as incision A,B, C and D respectively. The incision is started with a scalpel bladethrough the skin (epidermis and dermis). Each incision is deepenedthrough the subcutaneous tissues down to the linea alba. The HarmonicBlade HK105 is set at Power level 5 for cutting tissue and Power level 3for coagulating bleeders. Monopolar electrosurgery is set at 40 Wattscutting and 40 Watts coagulation with Blend 2/Spray coagulation.Electrosurgery is used in the cutting mode with the coagulation Blend2/Spray to coagulate bleeders. The linea alba is not incised.

Closure of the incision is effected by apposing the skin with 3-0 nylonin a simple interrupted pattern. Dermabond is applied to seal theepidermis. No bandages are applied to the incisions.

After three days, the pigs are euthanized and each incision site isremoved enbloc from the abdominal wall. The tissue block is slicedperpendicular to the surgical incision to create slabs about 4-6 mmthick. The slab is trimmed to remove the skin from the top and musclefrom the bottom of the sample. The side walls are trimmed toapproximately 4 mm from the surgical incision leaving a rectangularblock of subcutaneous fatty tissue. Four to six samples are taken fromeach incision site and from a control site which had not previously beenincised. Samples are placed in sterile DNAse-, RNAse-, protein-freeEppendorf tubes, flash frozen in liquid nitrogen (LN₂), and then held ondry ice throughout tissue collection. The samples are stored in a −80°C. freezer.

Total protein is isolated in quadruplicate from tissue (four each ofcontrol, electrosurgery, and Harmonic). The samples are weighed andweights are normalized relative to that of the smallest sample. Samplesare ground in liquid nitrogen in a mortar and pestle and collected innew tubes. Proteins are extracted from the samples using a differentialdetergent fractionation (DDF) procedure. This results in four proteinfractions (cytosolic, membrane/organelle, nuclear and least soluble) foreach sample to provide a total of 48 samples to be analyzed bynano-spray 2-dimensional liquid chromatography tandem mass spectrometry(2-D LC MS2). Each DDF is then precipitated in 50% trichloroacetic acid(½ volume, 30 min) and washed twice in ice-cold acetone (ACN) to removesalts and detergents. Protein pellets are resuspended in 100 mM ammoniumbicarbonate, 5% HPLC grade acetonitrile, reduced (5 mM dithiothreitol,65 C, 10 min), alkylated (10 mM iodoacetamide, 37° C., 30 min) anddigested to complete dissolution with trypsin (1:50 w/w, 37 ° C., 36hrs).

The tryptic digests are then centrifuged (13,000 g) and supernatantsspin-filtered (0.45 μm filter; Ultrafree MC, Millipore). Theflow-through is dried out in vacuum centrifuge and resuspended in 250 μlof 2% ACN, 0.1% FA. The samples are further desalted using the PeptideMacro Trap TR1/25108/52 (Michrom Bioresources). Eluted peptides aredried again, and dissolved in 22 μl of 5% ACN and 0.1% formic acid.Twenty microliters of the filtrated peptide mixtures are subjected to2-D LC MS2. The reverse-phase column (BioBasic C18, 0.18×100-mm ThermoHypersil-Keystone) is coupled directly in-line with the electro-sprayionization ion trap mass spectrometer equipped with nano-spray sourceand a column flow rate of 500 nl/min used. The peptides are eluted fromRP column by acetonitrile gradient (in 0.1% FA) of 5%-50% for 580 min,95% for 20 min, 5% for 25 min, a total of 625 min elution. The massspectrometer is configured to collect the spectral data by alternatingbetween a single full MS scan followed by three MS-MS scans on the threemost intense precursor masses from the full MS scan. The collisionenergy is normalized to 35%, the dynamic mass exclusion windows are 2minutes long. MS spectra are measured with an overall mass/charge (m/z)range of 300 to 1,700.

The database of all known porcine genes and human orthogs is used forsearching mass spectra using TurboSEQUEST Cluster v. 3.3 SR1.Isotope-free quantitative analysis is used and is based on spectralcounting combined with the increased specificity given by including thequantitative aspects of the Sequest cross correlation (XCorr). Decoydatabase searching is used in order to calculate the probability that atandem mass spectrometry match occurred by chance and, from these, theprobability of the protein identification occurring by chance. Onlypeptides that are identified at p≦0.05 are used for proteinidentifications. For differential protein expression analysis, MonteCarlo resampling and multiple testing corrections are employed using theBenjamini-Hochberg method.

The measured levels of decreased proteins as given by the sum of thecross correlation is given for Electrosurgery, Harmonic, and Control inthe following table 8.

TABLE 8 Decreased Proteins Sum of Cross Correlation Acronym Gene NameElectrosurgery Harmonic Control ALB Albumin 3442.3 5533.6 12052.4 FASNFatty acid synthase 61.8 226.3 668.4 FABP4 Fatty acid binding protein 440.9 149.3 622.2

The protein levels compared to Control are all decreased more forElectrosurgery than for Harmonic. This quantitative result is inagreement with qualitative observations made over a much longer durationthat the Harmonic device produces less tissue trauma and better woundhealing than Electrosurgery. Hence these biomarkers are useful for fast,quantitative assessment of the quality of the surgical device.

EXAMPLE 5 Evaluation of the Combination of a Surgical Device and aVasoconstrictor

A Harmonic Blade (by Ethicon Endo-Surgery, Inc. of Cincinnati, Ohio) isused to create an incision in tissue while the tissue is irrigated withan 0.5% phenylephrine HC1 solution. A separate incision is made with theHarmonic Blade alone. The incisions are closed and three days latersamples are extracted at the incision site. The samples are assayed forthe proteins hemoglobin beta, hemoglobin alpha and prolyl endopeptidase.Lower levels of analytes for one of the two samples indicates a superiormethod of treatment.

EXAMPLE 6 Evaluation of the Combination of a Surgical Device and aCorticosteroid

A Harmonic Blade (by Ethicon Endo-Surgery, Inc. of Cincinnati, Ohio) isused to create an incision in tissue while the tissue is irrigated withan 0.05% dexamethasone solution. A separate incision is made with theHarmonic Blade alone. The incisions are closed and three days latersamples are extracted at the incision site. The samples are assayed formRNA for CXCL6, IL8 and CXCL2. Lower levels of analytes for one of thetwo samples indicates a superior method of treatment.

EXAMPLE 7 Evaluation of the Combination of a Surgical Device and anNsaid

A Harmonic Blade (by Ethicon Endo-Surgery, Inc. of Cincinnati, Ohio) isused to create an incision in tissue while the tissue is irrigated withan 0.1% sodium naproxen solution. A separate incision is made with theHarmonic Blade alone. The incisions are closed and three days latersamples are extracted at the incision site. The samples are assayed forIL8 and IL6. Lower levels of analytes for one of the two samplesindicates a superior method of treatment.

EXAMPLE 8 Combination Device for Dissection and Dna Delivery

A Harmonic Blade (by Ethicon Endo-Surgery, Inc. of Cincinnati, Ohio) isused to create an incision in tissue while the tissue is irrigated withDNA for TGF-β (20 μg total) ensconced in Optison (GE Healthcare, LittleChalfont, Buckinghamshire, UK). The Harmonic Blade acts both as a tissuescalpel and a cell poration device. A separate incision is made with theHarmonic Blade alone. The incisions are closed and three days latersamples are extracted at the incision site. The samples are assayed forIL8 and IL6. Lower levels of analytes for one of the two samplesindicates a superior method of treatment.

It should be appreciated from the foregoing that various types ofbiomarkers may be monitored, quantified, and/or otherwise processed oranalyzed to evaluate the type and/or degree of trauma caused to tissue(and/or to evaluate other types of biological effects) by various typesof surgical instruments. It should also be appreciated from theforegoing that such evaluations of effects caused by surgicalinstruments may be used to evaluate the efficacy of the surgicalinstruments. In addition, it should be understood that biomarker relateddata may be used to evaluate a particular patient's susceptibility totrauma, propensity for pain/bleeding/healing/revascularization, and/orother biological traits of the particular patient, in addition to or inlieu of being used to evaluate the efficacy of surgical instruments. Theevaluation of the efficacy of a surgical instrument and/or theevaluation of biological traits of a particular patient may in turninfluence decisions on which surgical instruments to use in particularprocedures, how to modify the surgical instruments in subsequentdesigns, how to modify the use of a given surgical instrument, decisionsregarding use of therapeutic agents, and/or various other types ofdecisions. Other types of decisions that biomarker related evaluationsmay influence, as well as ways in which biomarker related evaluationsmay influence those decisions, will be apparent to those of ordinaryskill in the art in view of the teachings herein.

V. Exemplary Implementation of Biomarker Monitoring Principles inMedical Devices

While examples discussed above include conventional steel scalpels,ultrasonic scalpels, and electrosurgical scalpels, it should beunderstood that the systems and methods described herein may also beapplied to a variety of types of surgical instruments. By way of exampleonly, the systems and methods described herein may be applied to any ofthe following types of devices: non-energized cutting devices (e.g.,scalpels, scissors, etc.); electrosurgical devices (e.g., monopolar orbipolar devices, such as the ENSEAL device by Ethicon Endo-Surgery, Inc.of Cincinnati, Ohio, etc.); ultrasonic devices (e.g., the HARMONICseries of ultrasonic devices by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio, etc.); surgical stapling devices (e.g., the ECHELON,CONTOUR, or PROXIMATE series of stapling devices by EthiconEndo-Surgery, Inc. of Cincinnati, Ohio, etc.); trocar devices (e.g., theENDOPATH XCEL series of trocars by Ethicon Endo-Surgery, Inc. ofCincinnati, Ohio, etc.); hand ports (e.g., the ENDOPATH DEXTRUS seriesof hand ports by Ethicon Endo-Surgery, Inc. of Cincinnati, Ohio, etc.);other types of access devices (e.g., the SSL access device by EthiconEndo-Surgery, Inc. of Cincinnati, Ohio, etc.); clip applying devices(e.g., the LIGAMAX or LIGACLIP series of biopsy devices by EthiconEndo-Surgery, Inc. of Cincinnati, Ohio, etc.); liposuction/tissuesuction devices (e.g., ultrasonic liposuction/tissue suction devices orother types, etc.); hard tissue cutting devices (e.g., saws, drills,shavers, etc.); and/or other types of surgical instruments. The methodsdescribed herein may also be applicable to any chemical or physicalmechanism used to effect surgical procedures, including use ofelectromagnetic radiation such as radiofrequency, microwave (MASER),infrared, visible (LASER), ultraviolet, x-ray and gamma-ray; sonic orultrasonic sound waves; fluidics, such as water jets; pneumatics;chemical agents such as acidic or caustic materials, etc. Additionalapplicable surgical instruments may include HIFU devices or potentiallysome of the wound healing/enhancing ultrasonic devices such as thoseused to aid in bone healing. Various other types of surgical instrumentsto which the systems and methods described herein may be applied, aswell as various ways in which the systems and methods described hereinmay be applied to such surgical instruments, will be apparent to thoseof ordinary skill in the art in view of the teachings herein.

In addition, while the foregoing examples relate mainly to traumacreated by surgical instruments, it should be understood that biomarkersmay be monitored, quantified, and/or otherwise processed or analyzed toevaluate the type and/or degree of trauma (and/or other types ofbiological effects) caused to tissue by other types of medical devicesthat may not be considered “surgical instruments.” By way of exampleonly, the systems and methods described herein may be applied to any ofthe following types of devices: sutures; surgical staples (e.g., staplesfrom any of the above-mentioned stapling devices, among others);surgical clips (e.g., clips from any of the above-mentioned clipapplying devices, among others); gastric bands (e.g., the REALIZEgastric band by Ethicon Endo-Surgery, Inc. of Cincinnati, Ohio, and itsassociated components, etc.); stents (e.g., any type of stent device byCordis Corporation of Bridgewater, N.J., etc.); prosthetics (e.g., anytype of prosthetic device by DePuy Orthopaedics, Inc. of Warsaw, Ind. orDePuy Spine, Inc. of Raynham, Mass. or DePuy Mitek, Inc. of Raynham,Mass., etc.); implantable drug infusion devices; cardiovascularimplants, such as pacemakers; neurological stimulators or inhibitors;closed suction drain systems; low vacuum wound healing systems; and/orother types of implanted devices. Various other types of medical devicesto which the systems and methods described herein may be applied, aswell as various ways in which the systems and methods described hereinmay be applied to such medical devices, will be apparent to those ofordinary skill in the art in view of the teachings herein.

A. Exemplary Devices for Capture of Biomarker Data

Several ways in which biomarker data may be captured have already beendescribed herein. However, FIGS. 2-7 show additional specific yet merelyillustrative examples of how biomarker data may be captured. Thefollowing examples are provided in the context of a harmonic surgicalinstrument. By way of example only, the teachings below may be readilyapplied to a harmonic surgical instrument as shown and described in U.S.Pub. No. 2006/0079874, entitled “Tissue Pad for Use with an UltrasonicSurgical Instrument,” published Apr. 13, 2006, the disclosure of whichis incorporated by reference herein. As another example, the teachingsbelow may be readily applied to a harmonic surgical instrument as shownand described in U.S. Pub. No. 207/0191713, entitled “Ultrasonic Devicefor Cutting and Coagulating,” published Aug. 16, 2007, the disclosure ofwhich is incorporated by reference herein. As yet another example, theteachings below may be readily applied to a harmonic surgical instrumentas shown and described in U.S. Pub. No. 2007/0282333, entitled“Ultrasonic Waveguide and Blade,” published Dec. 6, 2007, the disclosureof which is incorporated by reference herein. As still another example,the teachings below may be readily applied to a harmonic surgicalinstrument as shown and described in U.S. Pub. No. 2008/0200940,entitled “Ultrasonic Device for Cutting and Coagulating,” published Aug.21, 2008, the disclosure of which is incorporated by reference herein.Still other suitable types of harmonic surgical instruments to which thebelow teachings may be readily applied will be apparent to those ofordinary skill in the art in view of the teachings herein. It should beunderstood that, in some versions, harmonic surgical instruments mayprovide sonoporation capabilities that facilitate gene therapy withoutthe use of viral carriers. Exemplary uses of harmonic surgicalinstruments for gene therapy through sonoporation will be described ingreater detail below in section V.D. Thus, it should be understood thatin some versions, a single harmonic device may be used to both obtainbiomarker data as described in section V.A. and administer a genetherapy (or other form of therapy/treatment/etc.) based at least in parton such biomarker data.

It is also contemplated that the below teachings may be readily appliedto various other kinds of medical devices, including but not limited tosurgical instruments, medical implants, etc. For instance, the belowteachings may be readily applied to virtually any of the kinds ofmedical devices that are referred to herein. Still other suitabledevices to which the below teachings may be readily applied will beapparent to those of ordinary skill in the art in view of the teachingsherein. It should therefore be understood that the below examplesinclude harmonic surgical instruments by way of illustration only, andthat the below teachings are not intended to be limited to just harmonicsurgical instruments.

It should also be understood that once biomarker data is acquired,either in accordance with the below teachings or otherwise, informationfrom that biomarker data may be used in various ways. For instance,various examples of what may be done with information from biomarkerdata are described in greater detail elsewhere herein (e.g., sectionV.B., section V.C., and section V.D., below). Still other suitableexamples of what may be done with information from biomarker data willbe apparent to those of ordinary skill in the art in view of theteachings herein.

1. Exemplary Device for Capture and Retention of Biomarkers forSubsequent Analysis

FIG. 2 shows an exemplary device (100) that may be used to capture andretain biomarker data. In the present example, device (100) isessentially a modified version of the harmonic surgical instrument shownand described in U.S. Pub. No. 2006/0079874, though device (100) may ofcourse have any other suitable features, components, and/orconfigurations, etc. Device (100) of this example has a handle portion(110) including a pistol grip (112). A shaft (120) extends distally fromhandle portion (110). An end effector (130) is disposed at the distalend of shaft (120). End effector (130) includes an harmonic blade (132)and a clamp pad (134). Harmonic blade (132) is operable to vibrate oroscillate at ultrasonic frequencies (e.g., 55.5 kHz). An ultrasonictransducer (140) is disposed in handle portion (110) and drives harmonicblade (132) through a waveguide (not shown) that is disposed in shaft(120). Ultrasonic transducer (140) receives power from a generator viacable (146). Buttons (142, 144) are operable to selectively activateharmonic blade (132). For instance, one button (142) may provide maximumintensity while the other button (144) provides minimum intensity.Device (100) of this example is configured such that either button (142,144) must be held down in order to keep ultrasoninc blade (132) in anactive state, such that harmonic blade (132) returns to an inactivestate as soon as a held button (142, 144) is released.

Clamp pad (134) is operable to pivot relative to harmonic blade (132),such as to selectively clamp tissue between clamp pad (134) and harmonicblade (132). In particular, clamp pad (134) is coupled with triggermember (150), which pivots relative to pistol grip (112). A user maythus squeeze trigger member (150) toward pistol grip (112) to pivotclamp pad (134) toward harmonic blade (132) and release trigger member(150) to pivot clamp pad (134) away from harmonic blade (132). In someversions, trigger member (150) is resiliently biased to the positionshown in FIG. 2, whereby clamp pad (134) is pivoted away from harmonicblade (132).

As shown in FIG. 3, device (100) of this example includes a suction port(160) at end effector (130). Its position at end effector (130) allowssuction port (160) to directly draw mist at a wound site as harmonicblade (132) is activated to create the wound and/or to otherwise addressthe wound (e.g., blade (132) activated to stop bleeding at the wound,etc.). Suction port (160) is at the distal end of a conduit (162), whichextends along the full length of shaft (120). A suction pump (170),which is positioned in handle portion (110), is in fluid communicationwith conduit (162), such that suction pump (170) is operable to drawsuction through suction port (160). Suction pump (170) receives powervia cable (146). In some versions, suction pump (170) is incommunication with buttons (142, 144), such that suction pump (170) isselectively activated/deactivated simultaneously with harmonic blade(132). In some such versions, a control logic activates suction pump(170) as soon as harmonic blade (132) is activated; yet keeps suctionpump (170) activated for a certain time period following deactivation ofa previously activated harmonic blade (132), allowing suction pump (170)and suction port (160) to draw in any additional mist that may be stillemanating or lingering shortly after harmonic blade (132) has beendeactivated. In some other versions, a separate button is provided forsuction pump (170), such that suction pump (170) may be activatedindependently of harmonic blade (132). It should also be understood thatsuction pump (170) may be omitted, and device (100) may include afeature for coupling with an external source of suction/vacuum.

As also shown in FIG. 2, device (100) of the present example includes acapture vessel (180) in communication with conduit (162). In particular,capture vessel (180) is configured to receive and retain cell fragmentsand/or other biological materials that are picked up in mist drawnthrough suction port (160). Capture vessel (180) is removable fromhandle portion (110), such that after a surgical procedure is complete,capture vessel (180) may be taken to a biomarker testing system toprocess biomarkers embodied in the cell fragments and/or otherbiological materials that are contained in capture vessel (180). By wayof example only, biological materials that are contained in capturevessel (180) may be processed in accordance with the teachings of FIG. 1and the corresponding written description, in accordance with any otherteachings herein, and/or in accordance with any other methods as will beapparent to those of ordinary skill in the art in view of the teachingsherein. Capture vessel (180) is configured to maintain the integrity ofmaterials contained therein, allowing those materials to be processed atsome time after their capture. In some versions, device (100) includesone or more additional features that are configured to at leastpartially process biological materials before they reach capture vessel(180) and/or once they reach capture vessel (180). Various suitablecomponents, features, configurations, and operabilities of capturevessel (180) will be apparent to those of ordinary skill in the art inview of the teachings herein. Similarly, various suitable ways in whichdevice (100) may be otherwise modified will be apparent to those ofordinary skill in the art in view of the teachings herein.

2. Exemplary System for Capture and Analysis of Biomarkers in Real Time

FIG. 4 shows an exemplary system (200) that may be used to capture andprocess biomarker data in real time or near-real time. System (200) ofthis example includes a harmonic surgical instrument (210), a biomarkerprocessing module (230), and a harmonic generator (298). Harmonicsurgical instrument (210) of this example is similar in several ways todevice (100) described above. In particular, harmonic surgicalinstrument (210) of the present example is essentially a modifiedversion of the harmonic surgical instrument shown and described in U.S.Pub. No. 2006/0079874, though harmonic surgical instrument (210) may ofcourse have any other suitable features, components, and/orconfigurations, etc. Harmonic surgical instrument (210) of this exampleincludes a handle portion (212), a shaft (214) extending distally fromhandle portion (212), and an end effector (216) positioned at the distalend of shaft (214). End effector (216) includes an harmonic blade (218)and a pivoting clamp member (220). A trigger member (222) is operable toselectively pivot clamp member (220), while buttons (224, 226) areoperable to selectively activate harmonic blade (218). End effector(216) of this example also includes a suction port (not shown), muchlike suction port (160) shown in FIG. 3. A cable (299) couples harmonicsurgical instrument (210) with harmonic generator (298), which isoperable to energize an ultrasonic transducer (not shown) in handleportion (212) to activate harmonic blade (218). A conduit (228) is alsocoupled with handle portion (212). Conduit (228) is configured tocommunicate a mist drawn in by the suction port at end effector (216) tobiomarker processing module (230). While biomarker processing module(230) is shown as being a component that is separate from (but tetheredto) harmonic surgical instrument (210) in this example, it should beunderstood that harmonic surgical instrument (210) may be readilymodified to include biomarker processing module (230) on board (e.g.,within handle portion (212), on handle portion (212), etc.).

Biomarker processing module (230) of the present example is operable toperform at least some of the processing shown in FIG. 1 and described ingreater detail above. Of course, it should be understood that biomarkerprocessing module (230) may be operable to perform various other kindsof processing. In the present example, biomarker processing module (230)includes a filter and dilution stage (232), an enzyme cleave stage(234), a biomarker sensor (250), a reservoir (236), and a suction source(238). Suction source (238) is operable to draw a mist through thesuction port at end effector (216) during use of harmonic surgicalinstrument (210), and to continue drawing that mist (and saline and/orother fluids) through biomarker processing module (230) in accordancewith block (10) of FIG. 1. While suction source (238) is shown as beingan integral component of biomarker processing module (230), it should beunderstood that suction source (238) may be external to biomarkerprocessing module (230) in some versions. Reservoir (236) is configuredto collect and retain fluids that are communicated along the fluid pathpast biomarker sensor (250). Reservoir (236) may be removable frombiomarker processing module (230). In addition, one or more filters maybe provided to substantially isolate suction source (238) from liquidsand/or debris during operation of biomarker processing module (230). Insome other versions, no filters are used with respect to suction source(238). It should also be understood that reservoir (236) may be anintegral part of suction source (238) or may even be omitted altogether.

As noted above with respect to the process shown in FIG. 1, saline maybe used while processing biomarkers. To that end, biomarker processingmodule (230) of the present example includes a saline source (240)coupled with filter and dilution stage (232). Filter and dilution stage(232) may also include one or more features that are configured toprovide ultrasonic sieving, electrostatic sieving, and/or some othertype of filtering of the mist passing through filter and dilution stage(232). Filter and dilution stage (232) is thus operable to filter anddilute the mist in accordance with block (20) of FIG. 1 as the mistproceeds toward biomarker sensor (250). Various suitable components,features, and configurations that may be included in filter and dilutionstage (232) will be apparent to those of ordinary skill in the art inview of the teachings herein. Of course, as with other componentsdescribed herein, filter and dilution stage (232) may be modified,substituted, supplemented, or even omitted, as desired.

In the present example, after being filtered and diluted, the mistreaches enzyme cleave stage (234), which is operable to cleavebiomarkers in the mist with enzymes in accordance with block (30) ofFIG. 1 as the mist continues to proceed toward biomarker sensor (250).Various suitable components, features, and configurations that may beincluded in enzyme cleave stage (234) will be apparent to those ofordinary skill in the art in view of the teachings herein. Of course, aswith other components described herein, filter and dilution stage (232)may be modified, substituted, supplemented, or even omitted, as desired.

Exemplary components for sensor (250) are shown in greater detail inFIGS. 6-7. In particular, sensor (250) of the present example includes acantilever beam (252) extending outwardly from a shaft (254). Beam (252)is positioned within the main conduit (256) of biomarker processingmodule (230). Mist particles (260) flow through main conduit (256) asindicated by arrow (262), flowing across beam (252). In some versions,beam (252) includes one or more particular antibodies selected toattract specific complementary antigens/proteins (264) that serve asuseful biomarkers in mist particles (260). In addition or in thealternative, beam (252) may include one or more particular nucleotidebase pair sequence amino acids selected to attract specificcomplementary nucleotide sequences (e.g., gene fragments) that serve asuseful biomarkers in mist particles (260). Various suitable ways inwhich such antibodies and/or nucleotide base pair sequence amino acidsmay be provided on beam (252) will be apparent to those of ordinaryskill in the art in view of the teachings herein. It should also beunderstood that antibodies and/or nucleotide base pair sequence aminoacids may be provided on beam (252) as microdot arrays. In addition, itshould be understood that antibodies and nucleotide base pair sequenceamino acids are just two examples of things that may be provided on beam(252) to attract biomarkers. Other suitable things that may be providedon beam (252) to attract biomarkers (or otherwise be sensitive tobiomarkers) will be apparent to those of ordinary skill in the art inview of the teachings herein.

Furthermore, it should be understood that a plurality of beams (252) maybe provided in main conduit (256), each beam (252) having its own shaft(254). Regardless of whether just a single beam (252) or more than onebeam (252) is provided in main conduit (256), it should be understoodthat any given beam (252) may be formulated to attract just onebiomarker or a combination of biomarkers. Thus, in some versions,several beams (252) are used, such that sensor (250) is capable ofdetecting several different biomarkers substantially simultaneously. Inversions where sensor (250) is capable of detecting several differentbiomarkers, biomarker processing module (230) may be configured to allowa user to selectively activate only certain beams (252) to selectivelydetect only one or only some of the kinds of biomarkers that biomarkerprocessing module (230) is capable of detecting. For instance, sensorreader (270) within biomarker processing module (230) may be configuredto only take readings from just one or just some of the beams (252)based on user input. As another merely illustrative example, mainconduit (256) may be branched into separate sub-conduits via a manifold,each sub-conduit having its own one or more beams (252) dedicated todetection of specific respective biomarkers or specific respectivecombinations of biomarkers. In some such versions, biomarker processingmodule (230) may be configured to selectively provide communication ofthe mist through only those sub-conduits associated with specificbiomarkers (or biomarker combinations) specified by the user, such as bycontrolling a system of valves or gates to distribute the mist based onuser selections. Other suitable ways in which a biomarker processingmodule (230) that is sensitive to different kinds of biomarkers may becarried out will be apparent to those of ordinary skill in the art inview of the teachings herein.

As beam (252) picks up biomarkers from mist particles (260), themass/weight of beam (252) increases. The results of this effect may beemphasized by concentrating the antibodies and/or nucleotide base pairsequence amino acids, etc. at or near the free end (258) of beam (252).In some versions, beam (252) is substantially rigid, the couplingbetween beam (252) and shaft (254) is substantially rigid, and shaft(254) is rotatable within main conduit (256) about the longitudinal axisof shaft (254). Thus, as the weight of beam (252) increases frombiomarkers being picked up by beam (252), beam (252) and shaft (254)begin to pivot downwardly within main conduit (256). In some suchversions, sensor reader (270) within biomarker processing module (230)is able to sense such rotation of shaft (254). In some other versions,beam (252) is substantially rigid, the coupling between beam (252) andshaft (254) is substantially rigid, and shaft (254) is not rotatablewithin main conduit (256). Thus, as the weight of beam (252) increasesfrom biomarkers being picked up by beam (252), the torsional stress onshaft (254) increases, and the acoustic resonant frequency of shaft(254) changes. Sensor reader (270) may thus be configured to sense thechanged torsional stress and/or changed acoustic resonant frequency ofshaft (254). As another merely illustrative example, shaft (254) mayflex (without necessarily pivoting) as biomarkers gather on beam (252),and such flexing may be picked up by sensor reader (270). In still otherversions, beam (252) is substantially rigid, beam (252) is rotatableabout shaft (254), and shaft (254) is not rotatable within main conduit(256). Thus, as the weight of beam (252) increases from biomarkers beingpicked up by beam (252), beam (252) rotates about shaft (254). Sensorreader (270) may thus be configured to sense the rotation of beam (252)about shaft (254). As yet another merely illustrative example, beam(252) is flexible, the coupling between beam (252) and shaft (254) issubstantially rigid, and shaft (254) is not rotatable within mainconduit (256). Thus, as the weight of beam (252) increases frombiomarkers being picked up by beam (252), beam (252) begins to benddownwardly. Sensor reader (270) may thus be configured to sense thebending of beam (252). In some such versions, a strain gauge may beprovided on beam (252) to facilitate detection of bending. It shouldalso be understood that one or more reference sensors may also beincluded. Such reference sensors may be configured to respond toenvironmental conditions without capturing biomarkers (e.g., to improvesignal-to-noise ratio, etc.).

While the above description provides several merely illustrativeexamples of how different properties, configurations, and relationshipsof beam (252) and shaft (254) may yield different kinds of mechanicaleffects in response to biomarkers collecting on beam (252), it should beunderstood that there are various ways to detect and measure themechanical effects on beam (252) and/or shaft (254) as biomarkerscollect on beam (252). For instance, these mechanical effects may bedetected and measured optically (e.g., machine vision directed to one ormore optical markers on beam (252) and/or shaft (254), etc.),capacitively (e.g., monitoring changes in capacitance due to movement ofand/or stresses in beam (252) and/or shaft (254), etc.), acousitically(e.g., monitoring changes in acoustic resonant frequency of beam (252)and/or shaft (254), etc.), and/or otherwise. Other suitable ways inwhich the mechanical effects of biomarker collection on beam (252) maybe detected and measured will be apparent to those of ordinary skill inthe art in view of the teachings herein. In the present example,processing hardware (272) in sensor reader (270) includes the necessaryhardware (together with any monitoring hardware in sensor (250) itself)to detect and monitor the mechanical changes and convert suchinformation into information that is usable by the user and/or one ormore additional components of system (200).

In some settings, it may be desirable to clean sensor (250) byeffectively washing away biomarkers that have collected on beam (252).For instance, sensor (250) may eventually become essentially saturatedwith biomarkers to the point where it loses sensitivity oreffectiveness, such that it is necessary to “recharge” sensor (250).This may become desirable during a single session of use of system (200)for a single patient/subject. In addition or in the alternative, inversions where biomarker processing module (230) is configured to bereusable for several different use sessions (e.g., for the samepatient/subject and/or for different patients/subjects), it may bedesired to clear out sensor (250) between use sessions. There arevarious ways in which sensor (250) may be cleaned for re-use. Forinstance, as shown in FIG. 7, a saline wash (266) may be used to freeantigens/proteins (264) and/or nucleotide sequences (e.g., genefragments), etc. from beam (252). In some versions, saline wash (266) isprovided at a temperature that both differs from the temperature of theoriginal mist and is selected to free antigens/proteins (264) and/ornucleotide sequences (e.g., gene fragments), etc. from beam (252). Inaddition or in the alternative, antigens/proteins (264) and/ornucleotide sequences (e.g., gene fragments), etc. may be substantiallycleared from beam (252) electrostatically and/or by changing the pH ofthe flow over beam (252). Other suitable ways in which antigens/proteins(264) and/or nucleotide sequences (e.g., gene fragments), etc. may besubstantially cleared from beam (252) will be apparent to those ofordinary skill in the art in view of the teachings herein. Onceantigens/proteins (264) and/or nucleotide sequences (e.g., genefragments), etc. have been substantially cleared from beam (252), theantibodies and/or nucleotide base pair sequence amino acids, etc. remainon beam (252), such that sensor (250) may be re-used. Of course, sensor(250) may alternatively be configured such that sensor (250) is notre-usable.

It should also be understood that undesirably excessive buildup ofbiomarkers on beam (252) may be reduced or avoided by selectiveactivation or use of sensor (250). This may be accomplished by providingsuction from suction source (238) on a selective basis. For instance,the activation of suction source (238) may be tied to activation ofbuttons (224, 226) in a manner similar to that described above withrespect to device (100). In addition or in the alternative, the mist maybe selectively diverted upstream of biomarker processing module (230) orwithin biomarker processing module (230) before reaching sensor (250).For instance, the mist may be selectively diverted to reservoir (236)and/or to atmospheric air. Still other suitable ways in whichundesirably excessive buildup of biomarkers on beam (252) may be reducedor avoided will be apparent to those of ordinary skill in the art inview of the teachings herein.

In some versions, sensor (250) is provided at a MEMS scale size.Alternatively, sensor (250) may have any other suitable size.

Referring back to FIG. 5, and as noted above, sensor reader (270) iscoupled with sensor (250) and includes processing hardware (272) that isoperable to detect and monitor the mechanical changes and convert suchinformation into information that is usable by the user and/or one ormore additional components of system (200). Various suitable componentsthat may be incorporated into processing hardware (272) will be apparentto those of ordinary skill in the art in view of the teachings herein.Sensor reader (270) of the present example also includes a storagemedium (274) in communication with processing hardware (272). Storagemedium (274) may include volatile memory and/or non-volatile memory thatis accessed by processing hardware (272) to process data obtained fromsensor (250) (e.g., to check against tables stored in storage medium,etc.). In addition or in the alternative, storage medium (274) may storedata processed by processing hardware (272) for subsequent retrieval.

Sensor reader (270) of the present example also includes a communicationport (276) that is configured to communicate data from sensor reader(270) to an external device. For instance, communication port (276) maycommunicate biomarker related data to a desktop computer, laptopcomputer, smartphone, computer network, hospital mainframe, and/or otherdevice/system that may be used by a user and/or computer to view and/orprocess biomarker related information. As another merely illustrativeexample, communication port (276) may communicate data from sensorreader (270) to another medical device, such as a surgical instrument(e.g., any of the devices referred to in section V.B.1, section V.B.2,or section V.D., below, etc.), an implanted device (e.g., any of thedevices referred to in section V.C., below, etc.), an/or any other typeof device. Communication port (276) may be configured to provide suchcommunication via wire and/or wirelessly. It should also be understoodthat communication port (276) may be configured to receive incomingcommunications from an external device. For instance, communication port(276) may receive firmware updates for processing hardware (272),additional tables or other data for storage on storage medium (274),etc. Various other suitable configurations, operabilities, and uses forcommunication port (276) will be apparent to those of ordinary skill inthe art in view of the teachings herein. It should also be understoodthat, as with other components described herein, communication port(276) is merely optional and may simply be omitted if desired.

Biomarker processing module (230) of the present example also includes agraphical user interface (280) that is coupled with sensor reader (270).Graphical user interface (280) may thus be configured to presentbiomarker related information to a user. For instance, in accordancewith block (60) of FIG. 1, graphical user interface (280) may indicateto the user which kind of therapeutic agent to administer to thepatient, based on biomarker data obtained by biomarker processing module(230). In addition or in the alternative, in accordance with block (70)of FIG. 1, graphical user interface (280) may indicate to the user whichkind of surgical instrument to use on the patient, based on biomarkerdata obtained by biomarker processing module (230). In addition or inthe alternative, in accordance with block (80) of FIG. 1, graphical userinterface (280) may indicate to the user which kind of adjustmentsshould be made to a surgical instrument that will be used on thepatient, based on biomarker data obtained by biomarker processing module(230). In addition or in the alternative, in accordance with block (90)of FIG. 1, graphical user interface (280) may indicate to the user whichkind of surgical technique to use on a patient, based on biomarker dataobtained by biomarker processing module (230). Other suitable types ofinformation that may be presented to a user via graphical user interface(280) will be apparent to those of ordinary skill in the art in view ofthe teachings herein. It should also be understood that graphical userinterface (280) may be configured to receive input from the user,including but not limited to programming of processing hardware (272),selection of which biomarkers to detect, etc. Again, though, as withother components described herein, graphical user interface (280) ismerely optional and may simply be omitted if desired.

As with other components of system (200), the foregoing components,features, configurations, and operabilities of biomarker processingmodule (230) are merely illustrative examples. It should be understoodthat biomarker processing module (230) may alternatively have any othersuitable components, features, configurations, and/or operabilities.Other suitable components, features, configurations, and operabilitiesthat may be provided in biomarker processing module (230) will beapparent to those of ordinary skill in the art in view of the teachingsherein.

B. Exemplary Systems for Making Adjustments to SurgicalInstruments/Techniques Based on Biomarker Feedback

As noted above, feedback received through monitoring, analysis, or otherprocessing of biomarkers as described herein may be used to makeadjustments during a surgical procedure. In some situations, suchadjustments may be made in real time or in near-real time during thesurgical procedure. Furthermore, some such adjustments may be automatedas will be described in greater detail below. By way of example only,surgical adjustments made in response to biomarkers may include any orall of the following: adjusting the administration of active and/ortherapeutic agents; adjusting the operating parameters of a surgicalinstrument; and/or adjusting the technique by which a surgicalinstrument is used by a surgeon during a procedure. Several examples ofways in which surgical systems may provide adjustments based at least inpart on biomarker feedback are shown in FIGS. 8-11 and are described ingreater detail below, while various other examples will be apparent tothose of ordinary skill in the art in view of the teachings herein.

It should also be understood that biomarker influenced adjustments asdescribed below may be made based on various techniques for processingbiomarker data. For instance, an adjustment may be made when one or moredetected biomarker levels exceed a threshold. It should also beunderstood that adjustments may be made based on linear or nonlinearcombinations of several detected biomarker levels. For instance, controlalgorithms may provide one or more scores based on various permutationsof detected biomarker levels, and such scores may be used to provideadjustments as described below. Various suitable ways in which controlalgorithms may be formulated and based on various biomarker data pointswill be apparent to those of ordinary skill in the art in view of theteachings herein.

1. Exemplary System for Automatic Adjustments to Surgical InstrumentBased on Biomarker Feedback

As shown in FIG. 8, a surgical system (300) includes a biomarker sensor(301), a control module (302), and a surgical instrument (303). Surgicalsystem (300) of this example provides control of surgical instrument(303) based at least in part on biomarker expressions detected bybiomarker sensor (301). Biomarker sensor (301) is in communication withcontrol module (302), and is operable to communicate sensed biomarkerdata to control module (302). Control module (302) is in communicationwith surgical instrument (303), and is operable to control surgicalinstrument (303) based at least in part on biomarker data communicatedfrom biomarker sensor (301). While FIG. 8 shows biomarker sensor (301),control module (302), and surgical instrument (303) as separatecomponents, it should be understood that one or more of these componentsmay in fact be integrated into a single device. For instance, biomarkersensor (301) and control module (302) may be integral components ofsurgical instrument (303). As another merely illustrative example,control module (302) may be an integral component of surgical instrument(303) while biomarker sensor (301) is a separate component that isnevertheless in communication with control module (302). The componentsshown in FIG. 1 may also be provided in plural form. For instance,surgical system (300) may include two control modules (302)—one directlyassociated with biomarker sensor (301) and another directly associatedwith instrument (303)—with those two control modules (302) being incommunication with each other. It should also be understood thatcommunication between components may be provided in various ways,including but not limited to wired, wireless, or combinations of wiredand wireless.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may comprise one or more of the following:a biochip array, an immunoassay device, a spectrophotometry device, amass spectrometry device, a chromatographic device, a radioactivitymeasuring device, and/or any other suitable device or combination ofdevices. In some versions, biomarker sensor (301) monitors just one typeof biomarker. In some other versions, biomarker sensor (301) monitorsmore than one type of biomarker. For instance, biomarker sensor (301)may be configured to simultaneously monitor expressions of variousbiomarkers. Regardless of whether biomarker sensor (301) is used todetect expressions of just one biomarker or more than one biomarker, thetype(s) of biomarker(s) detected by biomarker sensor (301) may include(but need not be limited to) any of the types of biomarkers referred toherein. It should also be understood that biomarker sensor (301) mayinclude any or all of the components of biomarker processing module(230) and/or possible components. Other forms that biomarker sensor(301) may take will be apparent to those of ordinary skill in the art inview of the teachings herein.

Control module (302) may also take a variety of forms. In some versions,control module (302) comprises an integral component of instrument(303), such that control module (302) is located on or within instrument(303). In some other versions, control module (302) is located within apiece of capital equipment that is coupled with instrument (303). Instill other versions, control module (302) is formed by a combination ofone or more components located on or within instrument (303) as well asone or more component located on or within a piece of capital equipmentthat is coupled with instrument (303). By way of example only, controlmodule (302) may comprise a processor, such as a conventionalmicroprocessor or chip; or some other type of processor (e.g.,conventional, customized, etc.). Control module (302) may also comprisea memory, such as a flash memory device, a memory chip, or some othertype of memory. For instance, system (300) may be configured such that abiomarker related response should be provided through instrument (303)only when a certain biomarker level (or certain combination of levels ofdifferent biomarkers) exceeds or falls below a threshold level. Thus, aprocessor in control module (302) may include a control logic configuredto compare biomarker data from biomarker sensor (301) against one ormore threshold values stored in the memory of control module (302), andonly trigger a response through instrument (303) when the biomarker datafrom biomarker sensor (301) exceeds or falls below threshold data storedon the memory of control module (302); and/or when the biomarker dataotherwise meets some criteria defined in the memory.

In some other versions, biomarker data is not compared against one ormore baselines stored in memory in control module (302). For instance,biomarker sensor (301) may have a preconfigured sensitivity such that itsimply does not detect biomarker data (or does not otherwise communicatebiomarker data to control module (302)) unless one or more biomarkerexpression values exceed or fall below a threshold. Still other suitablerelationships between biomarker sensor (301) and control module (302),as well as various other ways in which control module (302) may processand react to biomarker data from biomarker sensor (301), will beapparent to those of ordinary skill in the art in view of the teachingsherein.

Instrument (303) may comprise any of the types of surgical instrumentsreferred to herein. Alternatively, instrument (303) may comprise anyother suitable type of surgical instrument. In versions where instrument(303) has an end effector that contacts the patient's tissue duringperformance of a surgical procedure, it should be understood thatbiomarker sensor (301) may be incorporated into or near such an endeffector or otherwise be in communication with one or more features ofend effector. In some versions, instrument (303) comprises anelectrosurgical instrument (e.g., monopolar or bipolar) having an endeffector that is configured to cut and coagulate tissue. In some suchversions, control module (302) is configured to adjust the frequencyand/or power level of energy that is applied through the end effector,based on biomarker feedback obtained through biomarker sensor (301). Forinstance, such biomarker feedback may relate to biomarker expressionsassociated with thermal damage to tissue, coagulation of blood, etc.Such adjustments may be made in real time or in near-real time (e.g.,control module (302) responsively adjusts frequency and/or power levelof instrument (303) immediately after processing biomarker data fromsensor (301), etc.).

In some other versions, instrument comprises an ultrasonic instrumenthaving an end effector that is configured to cut and coagulate tissue.Again, control module (302) may be configured to adjust the frequencyand/or power level of energy that is applied through the end effector,based on biomarker feedback obtained through biomarker sensor (301). Andagain, such biomarker feedback may relate to biomarker expressionsassociated with thermal damage to tissue, coagulation of blood, etc. Andas with the electrosurgical example, such ultrasonic adjustments may bemade in real time or in near-real time (e.g., control module (302)responsively adjusts frequency and/or power level of instrument (303)immediately after processing biomarker data from sensor (301), etc.).

As a merely illustrative example, biomarker sensor (301) may beconfigured to monitor levels of Tumor Necrosis Factor alpha (TNF-α), oneof the earliest mediators of an inflammatory response. If biomarkersensor (301) reports a level of (TNF-α) greater than previously observedhistorical norms, then control module (302) could decrease the energysupplied to the surgical device (303). As another merely illustrativeexample, biomarker sensor (301) may be configured to measure TNF-α, andcontrol module (302) or some other feature may be configured to measuretissue electrical resistance. If control module (302) observes thateither TNF-α levels or tissue electrical resistance are beyondhistorical norms, then control module (302) can decrease energy beingsupplied to the surgical device (303). As yet another merelyillustrative example, biomarker sensor (301) may be configured tomeasure TNF-α, and control module (302) or some other feature may beconfigured to measure pulse rate. If control module (302) observes thateither TNF-α levels or pulse rate are beyond historical norms, thencontrol module (302) can decrease energy being supplied to surgicaldevice (303).

Still other suitable forms that instrument (303) may take will beapparent to those of ordinary skill in the art in view of the teachingsherein. Similarly, other ways in which a biomarker sensor (301) may beused to adjust the operating parameters of a surgical instrument (303),in real time or otherwise, will be apparent to those of ordinary skillin the art in view of the teachings herein.

2. Exemplary System for Automatic Administration of Therapy Based onBiomarker Feedback

FIG. 9 shows a surgical system (310) that includes a biomarker sensor(301), a control module (302), a surgical instrument (303), and an agentadministration device (304). Surgical system (310) of this exampleprovides control of agent administration device (304) based at least inpart on biomarker expressions detected by biomarker sensor (301).Biomarker sensor (301) is in communication with control module (302),and is operable to communicate sensed biomarker data to control module(302). Control module (302) is in communication with agentadministration device (304), and is operable to control agentadministration device (304) based at least in part on biomarker datacommunicated from biomarker sensor (301). Optionally, control module(302) may also in communication with surgical instrument (303), muchlike in the example of surgical system (300) described above.

While FIG. 9 shows biomarker sensor (301), control module (302),surgical instrument (303), and agent administration device (304) asseparate components, it should be understood that one or more of thesecomponents may in fact be integrated into a single device. For instance,biomarker sensor (301), control module (302), and agent administrationdevice (304) may be integral components of surgical instrument (303). Asanother merely illustrative example, biomarker sensor (301) and controlmodule (302) may be an integral component of agent administration device(304) while instrument (303) is a completely separate component that isnot even in communication with control module (302). The componentsshown in FIG. 9 may also be provided in plural form. For instance,surgical system (310) may include two control modules (302)—one directlyassociated with biomarker sensor (301) and another directly associatedwith agent administration device (304)—with those two control modules(302) being in communication with each other. It should also beunderstood that communication between components may be provided invarious ways, including but not limited to wired, wireless, orcombinations of wired and wireless.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may be configured in accordance with theteachings provided above in the context of surgical system (300).Control module (302) may also take a variety of forms. By way of exampleonly, control module (302) may be configured in accordance with theteachings provided above in the context of surgical system (300). Insome versions, control module (302) controls agent administration device(304) based at least in part on biomarker data communicated frombiomarker sensor (301); such as when biomarker data from biomarkersensor (301) exceeds or falls below one or more threshold values and/orwhen the biomarker data otherwise meets some predefined criteria.Control module (302) may also control instrument (303) based at least inpart on biomarker data communicated from biomarker sensor (301); such aswhen biomarker data from biomarker sensor (301) exceeds or falls belowone or more threshold values and/or when the biomarker data otherwisemeets some predefined criteria. Still other suitable relationshipsbetween biomarker sensor (301) and control module (302), as well asvarious other ways in which control module (302) may process and reactto biomarker data from biomarker sensor (301), will be apparent to thoseof ordinary skill in the art in view of the teachings herein.

Instrument (303) may also take a variety of forms. By way of exampleonly, instrument (303) may be configured in accordance with theteachings provided above in the context of surgical system (300). Forinstance, instrument (303) may comprise any of the types of surgicalinstruments referred to herein. In versions where instrument (303) hasan end effector that contacts the patient's tissue during performance ofa surgical procedure, it should be understood that biomarker sensor(301) may be incorporated into or near such an end effector or otherwisecommunicate with a component at or near end effector. In some versions,control module (302) is configured to control instrument (303) based atleast in part on biomarker data communicated from biomarker sensor(301), as in the examples described above in the context of surgicalsystem (300). Such operability may be provided in addition to controlmodule (302) controlling agent administration device (304) based atleast in part on biomarker data communicated from biomarker sensor(301). Alternatively, control module (302) may just control agentadministration device (304) in some versions, without also controllinginstrument (303). In some such versions, instrument (303) may becontrolled in any suitable conventional fashion.

Agent administration device (304) may comprise a variety of types ofdevices that are operable to administer an active agent and/or atherapeutic agent to a surgical site. For instance, agent administrationdevice (304) may include some type of reservoir or other componentcontaining the agent, a nozzle or output port that is configured todispense the agent at the surgical site, and a pump or other componentthat is operable to drive the agent from the reservoir through thenozzle or port to the surgical site. In versions where instrument (303)has an end effector or other component that is placed into contact withor near tissue in a patient, a nozzle or output port of agentadministration device (304) may be positioned on or near such an endeffector or other component of instrument (303). Agent administrationdevice (304) may therefore administer one or more agents at an incision(before, during, and/or after the incision is created) and/or at someother type of surgical site. For instance, instrument (303) and/or agentadministration device (304) may be constructed in accordance with any ofthe teachings provided below in section V.D. The agent contained inagent administration device (304) may comprise coagulation agents,vasoconstrictors, anti-inflammatory agents, cell specific chemotacticagents, corticosteroids, NSAIDs, DNA, and/or any other suitable type ofagent(s). Other suitable agents that may be contained in agentadministration device (304) will be apparent to those of ordinary skillin the art in view of the teachings herein.

It should also be understood that agent administration device (304) maycontain more than one type of agent. In particular, agent administrationdevice (304) and control module (302) may be configured such thatparticular agents and/or combinations of agents are selected andadministered through agent administration device (304) based onbiomarker expressions detected through biomarker sensor (301). Forinstance, certain biomarker expressions may warrant administrations of acertain agent or a certain combination of agents. Control module (302)may include a memory storing “prescriptions” of agents, and a processorin control module (302) may include a control logic that is configuredto compare biomarker data from biomarker sensor (301) against suchprescriptions and select the prescription that best fits the biomarkerdata received from biomarker sensor (301). Control module (302) may thenexecute the selected prescription by commanding agent administrationdevice (304) to administer one or more agents to the surgical site,based on the selected prescription. Regardless of whether agentadministration device (304) simply provides one type of agent or allowsselection of more than one agent based on a prescription, etc.,administration of agents through agent administration device (304) maybe provided in real time or in near-real time (e.g., control module(302) responsively commands agent administration device (304) toadminister one or more agents immediately after processing biomarkerdata from sensor (301), etc.).

As a merely illustrative example, biomarker sensor (301) may be designedto measure total reactive oxygen species. If control module (302)observes a higher level of total reactive species than desired accordingto historical norms measured by biomarker sensor (301), then controlmodule (302) can either decrease the energy to surgical device (303) orrelease an antioxidizing agent, such as ascorbic acid, fromadministration device (304), or both. Another merely illustrativeexample would be where biomarker sensor (301) and agent administrationdevice (304) are implanted at the surgical site (or catheter ports areimplanted and in communication with an extracorporeal device). Biomarkersensor (301) then measures specific biomarkers for biological processessuch as inflammation and then instructs agent administration device(304) to release anti inflammatory agents based on the level ofbiomarker identified. Still other suitable forms that agentadministration device (304) may take (e.g., components, configurations,operability, etc.) will be apparent to those of ordinary skill in theart in view of the teachings herein. Similarly, other ways in which abiomarker sensor (301) may be used to control an agent administrationdevice (304), in real time or otherwise, will be apparent to those ofordinary skill in the art in view of the teachings herein.

3. Exemplary System for Biomarker Feedback to User via a SurgicalInstrument Feature

FIG. 10 shows a surgical system (320) that includes a biomarker sensor(301), a control module (302), and a surgical instrument (303). Surgicalsystem (320) of this example provides user feedback to a surgeonoperating instrument (303), based at least in part on biomarkerexpressions detected by biomarker sensor (301). Biomarker sensor (301)is in communication with control module (302), and is operable tocommunicate sensed biomarker data to control module (302). Controlmodule (302) is in communication with surgical instrument (303), and isoperable to provide user feedback to a surgeon through instrument (303),based at least in part on biomarker data communicated from biomarkersensor (301). While FIG. 10 shows biomarker sensor (301), control module(302), and surgical instrument (303) as separate components, it shouldbe understood that one or more of these components may in fact beintegrated into a single device. For instance, biomarker sensor (301)and control module (302) may be integral components of surgicalinstrument (303). As another merely illustrative example, control module(302) may be an integral component of surgical instrument (303) whilebiomarker sensor (301) is a separate component that is nevertheless incommunication with control module (302). The components shown in FIG. 10may also be provided in plural form. For instance, surgical system (320)may include two control modules (302)—one directly associated withbiomarker sensor (301) and another directly associated with instrument(303)—with those two control modules (302) being in communication witheach other. It should also be understood that communication betweencomponents may be provided in various ways, including but not limited towired, wireless, or combinations of wired and wireless.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may be configured in accordance with theteachings provided above in the context of surgical system (300).Control module (302) may also take a variety of forms. By way of exampleonly, control module (302) may be configured in accordance with theteachings provided above in the context of surgical system (300).Instrument (303) of the present example includes a user feedback feature(311), which is in communication with control module (302). Userfeedback feature (311) is configured to provide the surgeon with someform of feedback during use of instrument (303). Such feedback mayinclude audio, visual, and/or tactile feedback. For instance, userfeedback feature (311) may include one or more LEDs and/or other type(s)of visual feedback device; a speaker and/or other type(s) of audiofeedback device; and/or a vibrating device and/or other type(s) oftactile feedback device. User feedback feature (311) may provide one ormore of the various kinds of feedback described above with reference tographical user interface (280) and/or various other kinds of feedback.

In some versions, control module (302) controls user feedback feature(311) of instrument (303) based at least in part on biomarker datacommunicated from biomarker sensor (301); such as when biomarker datafrom biomarker sensor (301) exceeds or falls below one or more thresholdvalues and/or when the biomarker data otherwise meets some predefinedcriteria. Control module (302) may also control operational parametersof instrument (303) (e.g., frequency and/or power of energy appliedthrough instrument (303), etc.) based at least in part on biomarker datacommunicated from biomarker sensor (301); such as when biomarker datafrom biomarker sensor (301) exceeds or falls below one or more thresholdvalues and/or when the biomarker data otherwise meets some predefinedcriteria. Still other suitable relationships between biomarker sensor(301) and control module (302), as well as various other ways in whichcontrol module (302) may process and react to biomarker data frombiomarker sensor (301), will be apparent to those of ordinary skill inthe art in view of the teachings herein.

In addition to including user feedback feature (311), instrument (303)may be configured in accordance with the teachings provided above in thecontext of surgical system (300). For instance, instrument (303) maycomprise any of the types of surgical instruments referred to herein. Inversions where instrument (303) has an end effector that contacts thepatient's tissue during performance of a surgical procedure, it shouldbe understood that biomarker sensor (301) may be incorporated into ornear such an end effector or otherwise communicate with a component ator near end effector. In some versions, control module (302) isconfigured to control operational parameters of instrument (303) (e.g.,frequency and/or power of energy applied through instrument (303),etc.), based at least in part on biomarker data communicated frombiomarker sensor (301), as in the examples described above in thecontext of surgical system (300). Such operability may be provided inaddition to control module (302) controlling user feedback feature (311)based at least in part on biomarker data communicated from biomarkersensor (301). Alternatively, control module (302) may just control userfeedback feature (311) in some versions, without also controllingoperational parameters of instrument (303). In some such versions,operational parameters of instrument (303) may be controlled in anysuitable conventional fashion.

In the present example, it is up to the surgeon (or some other person)to react in accordance with feedback provided through user feedbackfeature (311). For instance, the surgeon may alter the technique throughwhich he or she is using instrument (303) in the surgical procedure,based at least in part on biomarker related feedback provided throughuser feedback feature (311). As a merely illustrative example, biomarkersensor (301) may be “tuned” to detect biomarkers associated withcancerous tumors. As a surgeon is operating near a cancerous tumor(e.g., to excise the tumor), it may be undesirable to sever, pierce, orotherwise compromise the structural integrity of the tumor itself withthe surgical instrument. Thus, a biomarker sensor (301) that is tuned todetect biomarkers associated with cancerous tumors may sense when ablade or other component of a surgical instrument is getting too closeto a tumor and may trigger an audio and/or visual alarm to the surgeonvia user feedback feature (311) in real time or near-real time to informthe surgeon that they are getting too close to the tumor. The surgeonmay alter his or her approach accordingly.

In addition or in the alternative, the surgeon (or some other person)may manually adjust the operating parameters of instrument (303), basedat least in part on biomarker related feedback provided through userfeedback feature (311). For instance, the surgeon (or some other person)may manipulate control features on instrument (303) and/or controlfeatures of a piece of capital equipment that is coupled with instrument(303) in response to biomarker related feedback provided through userfeedback feature (311). It should be understood that feedback may beprovided to the surgeon through user input feature (305) in real time ornear-real time. The surgeon (or other person) may thus alter thetechnique through which he or she is using instrument (303) in thesurgical procedure and/or manually adjust the operating parameters ofinstrument (303) in real time or near-real time, based at least in parton biomarker related feedback provided through user feedback feature(311).

4. Exemplary System for Biomarker Feedback to User via a Separate UserInterface

FIG. 11 shows an example of a surgical system (330) that is essentiallya variation of surgical system (320) described above. In particular,surgical system (330) includes a biomarker sensor (301), a controlmodule (302), and a surgical instrument (303). Surgical system (330) ofthis example also provides user feedback to a surgeon operatinginstrument (303), based at least in part on biomarker expressionsdetected by biomarker sensor (301). However, system (330) of thisexample includes a separate user feedback device (305) instead of havinga user feedback feature (311) incorporated into instrument (303). Inthis example, biomarker sensor (301) is in communication with controlmodule (302), and is operable to communicate sensed biomarker data tocontrol module (302). Control module (302) is in communication with userfeedback device (305), and is operable to control user feedback device(305) based at least in part on biomarker data communicated frombiomarker sensor (301). Optionally, control module (302) may also incommunication with surgical instrument (303), much like in the exampleof surgical system (300) described above.

While FIG. 11 shows biomarker sensor (301), control module (302), andsurgical instrument (303) as separate components, it should beunderstood that one or more of these components may in fact beintegrated into a single device. For instance, biomarker sensor (301)and control module (302) may be integral components of surgicalinstrument (303). As another merely illustrative example, control module(302) may be an integral component of surgical instrument (303) whilebiomarker sensor (301) is a separate component that is nevertheless incommunication with control module (302). The components shown in FIG. 11may also be provided in plural form. For instance, surgical system (330)may include two control modules (302)—one directly associated withbiomarker sensor (301) and another directly associated with instrument(303). It should also be understood that communication betweencomponents may be provided in various ways, including but not limited towired, wireless, or combinations of wired and wireless.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may be configured in accordance with theteachings provided above in the context of surgical system (300).Control module (302) may also take a variety of forms. By way of exampleonly, control module (302) may be configured in accordance with theteachings provided above in the context of surgical system (300).Similarly, instrument (303) may take any suitable form. For instance,instrument (303) may be configured in accordance with the teachingsprovided above in the context of surgical system (300). In addition,biomarker sensor (301) may be incorporated into instrument (303) asdescribed herein, if desired. It should also be understood that therelationships and interoperability between control module (302) and userfeedback device (305) may be the same as the relationships andinteroperability between control module (302) and user feedback feature(311) described above. Alternatively, control module (302) and userfeedback device (305) may have any other suitable relationships andinteroperability.

User feedback device (305) may also take a variety of forms. Like userfeedback feature (311) described above, user feedback device (305) isconfigured to provide the surgeon with some form of feedback during useof instrument (303). Such feedback may include audio, visual, and/ortactile feedback. By way of example only, user feedback device (305) maycomprise a conventional desktop computer; a conventional laptopcomputer; a portable electronic device (e.g., BlackBerry, iPhone, etc.);some other type of conventional device operable to provide audio,visual, and/or tactile feedback to a user; a customized device operableto provide audio, visual, and/or tactile feedback to a user; and/or anyother suitable type of device(s), including combinations thereof. Inaddition, user feedback device (305) (or some other component incommunication with user feedback device (305)) may be configured tostore biomarker related data and/or communicate such data over a networkto another location, such as for further analytical purposes,statistical purposes, and/or educational purposes, etc.

As with user feedback feature (311) described above, the surgeon (orsome other person) may react in accordance with feedback providedthrough user feedback device (305). For instance, the surgeon may alterthe technique through which he or she is using instrument (303) in thesurgical procedure, based at least in part on biomarker related feedbackprovided through user feedback device (305). As a merely illustrativeexample, the cancerous tumor example provided above with respect to userfeedback feature (311) may be equally applicable for user feedbackdevice (305). In addition or in the alternative, the surgeon (or someother person) may manually adjust the operating parameters of instrument(303), based at least in part on biomarker related feedback providedthrough user feedback device (305). For instance, the surgeon (or someother person) may manipulate control features on instrument (303) and/orcontrol features of a piece of capital equipment that is coupled withinstrument (303) in response to biomarker related feedback providedthrough user feedback device (305). It should be understood thatfeedback may be provided to the surgeon through user input device (305)in real time or near-real time. The surgeon (or other person) may thusalter the technique through which he or she is using instrument (303) inthe surgical procedure and/or manually adjust the operating parametersof instrument (303) in real time or near-real time, based at least inpart on biomarker related feedback provided through user feedback device(305).

In some versions of system (330), surgical instrument (303) is operatedby a surgeon and the surgeon receives feedback through user feedbackdevice (305). However, surgical instrument (303) may be controlled bythe patient instead in some versions. For instance, in one merelyillustrative alternative example, surgical instrument (303) comprises apatient-controlled iontophoresis device that may be activated by thepatient in response to something such as pain. In some such versions,biomarker sensor (301) is configured to sense certain biomarkers such asthose associated with the early onset of inflammation. In some versionsof this example, user feedback device comprises a portable electronicdevice such as a cell phone, iPhone, or Blackberry, etc. In addition,control module (302) may be configured to indicate to the patient,through their portable electronic device, to activate theiriontophoresis device. Still other ways in which feedback receivedthrough monitoring, analysis, or other processing of biomarkerexpressions as described herein may be used to make adjustments during asurgical procedure, in real time or otherwise, will be apparent to thoseof ordinary skill in the art in view of the teachings herein. It shouldbe understood from the foregoing that the systems (320, 330) describedabove with reference to FIGS. 10-11 may be useful in real surgicalscenarios with human patients or other types of patients. It should alsobe understood that the systems (320, 330) described above with referenceto FIGS. 10-11 may be useful in surgical training scenarios (e.g., wherean instrument (303) is being used in a lab-type setting, etc.). Forinstance, people training to become surgeons, training to improve theirsurgical skills, and/or training to learn how to use a particularinstrument (303) may be able to use feedback provided through userfeedback feature (311) or feedback device (305) to improve theirsurgical skills and techniques.

C. Exemplary Systems for Making Adjustments in Medical Implants Based onBiomarker Feedback

As another merely illustrative example, feedback received throughmonitoring, analysis, or other processing of biomarker expressions asdescribed herein may be used to automatically control or otherwiseaffect the operation of one or more devices that are implanted within apatient. Several examples of ways in which implanted device systems mayincorporate biomarker feedback are shown in FIGS. 12-14 and aredescribed in greater detail below, while various other examples will beapparent to those of ordinary skill in the art in view of the teachingsherein.

1. Exemplary Automatic Adjustment of Gastric Band Based on BiomarkerFeedback

FIG. 12 shows an adjustable gastric band system (340) that includes abiomarker sensor (301), a control module (302), an adjustable gastricband (306), and a pump/reservoir system (307). In the present example,biomarker sensor (301), control module (302), adjustable gastric band(306), and pump/reservoir system (307) are all implanted within apatient. Gastric band system (340) of this example provides adjustmentof gastric band (306) based at least in part on biomarker expressionsdetected by biomarker sensor (301). Biomarker sensor (301) is incommunication with control module (302), and is operable to communicatesensed biomarker data to control module (302). Control module (302) isin communication with pump/reservoir system (307), and is operable tocontrol pump/reservoir system (307) based at least in part on biomarkerdata communicated from biomarker sensor (301).

While FIG. 12 shows biomarker sensor (301), control module (302),adjustable gastric band (306), and pump/reservoir system (307) asseparate components, it should be understood that one or more of thesecomponents may in fact be integrated into a single device. For instance,biomarker sensor (301) may be an integral component of gastric band(306); with control module (302) being an integral component ofpump/reservoir system (307). The components shown in FIG. 12 may also beprovided in plural form. For instance, surgical system (340) may includetwo control modules (302)—one directly associated with biomarker sensor(301) and another directly associated with pump/reservoir system(307)—with those two control modules (302) being in communication witheach other. It should also be understood that communication betweencomponents may be provided in various ways, including but not limited towired, wireless, or combinations of wired and wireless.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may be configured in accordance with theteachings provided above in the context of surgical system (300).Control module (302) may also take a variety of forms. By way of exampleonly, control module (302) may be configured in accordance with theteachings provided above in the context of surgical system (300).Gastric band (306) may also take a variety of forms. For instance,gastric band (306) may comprise a fluid filled bladder that is coupledwith pump/reservoir system (307) via a catheter, forming a closed fluidcircuit. Gastric band (306) may be wrapped about a portion of apatient's stomach (e.g., the gastro-esophageal junction), and fluid maybe added to the fluid filled bladder to form a food intake restrictionstoma within the patient's stomach. Such a restricted stoma may form apouch in the patient's stomach, above gastric band (306), with such apouch having a smaller volume than the patient's stomach, such that thepatient experiences a relatively early sense of satiety duringconsumption of food. By way of example only, gastric band (306) may beconfigured in accordance with the teachings of U.S. Pat. No. 7,416,528,entitled “Latching Device for Gastric Band,” issued Aug. 26, 2008, thedisclosure of which is incorporated by reference herein. Other suitableforms that gastric band (306) may take will be apparent to those ofordinary skill in the art in view of the teachings herein.

Pump/reservoir system (307) of the present example is operable toselectively add fluid to (or withdraw fluid from) the bladder of gastricband (306), which will in turn affect the degree of restriction createdwithin the patient's stomach by gastric band (306). By way of exampleonly, pump/reservoir system (307) may be configured in accordance withthe teachings of U.S. Pat. No. 7,390,294, entitled “Piezo ElectricallyDriven Bellows Infuser for Hydraulically Controlling an AdjustableGastric Band,” issued Jun. 24, 2008, the disclosure of which isincorporated by reference herein. As another merely illustrativeexample, pump/reservoir system (307) may be configured in accordancewith the teachings of U.S. Pat. No. 7,351,240, entitled“Thermodynamically Driven Reversible Infuser Pump for Use as a RemotelyControlled Gastric Band,” issued Apr. 1, 2008, the disclosure of whichis incorporated by reference herein. Other suitable forms thatpump/reservoir system (307) may take will be apparent to those ofordinary skill in the art in view of the teachings herein.

In some versions, control module (302) controls pump/reservoir system(307) based at least in part on biomarker data communicated frombiomarker sensor (301); such as when biomarker data from biomarkersensor (301) exceeds or falls below one or more threshold values and/orwhen the biomarker data otherwise meets some predefined criteria. Forinstance, in some settings it may be desirable to adjust a gastric band(306) based on a degree of irritation of the tissue that is adjacent togastric band (306) and/or based on some other effect (e.g., strain,abrasion, perforation, etc.) on the tissue that is adjacent to gastricband (306). Accordingly, biomarker sensor (301) may be configured todetect biomarkers associated with such irritation (or other effects);and control module (302) may be configured to control pump/reservoirsystem (307) to loosen (or tighten) gastric band (306) based on thedetection of biomarker expressions that are associated with irritationof (or other effects on) tissue that is adjacent to gastric band (306).Such adjustments may be made in real time, in near-real time, orotherwise.

As another merely illustrative example, it may be desirable in somescenarios to relax the degree of restriction provided by gastric band(306) when the patient is between meals; and/or increase the degree ofrestriction provided by gastric band (306) when the patient is eating.Accordingly, biomarker sensor (301) may be configured to detectbiomarkers associated with fasting and/or consumption. In some suchversions control module (302) may be configured to controlpump/reservoir system (307) to loosen gastric band (306) based on thedetection of biomarker expressions that are associated with fastingand/or tighten gastric band (306) when biomarker expressions that areassociated with fasting are no longer detected. In addition or in thealternative, control module (302) may be configured to controlpump/reservoir system (307) to tighten gastric band (306) based on thedetection of biomarker expressions that are associated with eatingand/or loosen gastric band (306) when biomarker expressions that areassociated with eating are no longer detected. Again, such adjustmentsmay be made in real time, in near-real time, or otherwise.

As yet another merely illustrative example, it may be desirable in somescenarios to relax the degree of restriction provided by gastric band(306) when the patient is sleeping; and/or increase the degree ofrestriction provided by gastric band (306) when the patient is awake.Accordingly, biomarker sensor (301) may be configured to detectbiomarkers associated with sleep and/or a wakened state. In some suchversions control module (302) may be configured to controlpump/reservoir system (307) to loosen gastric band (306) based on thedetection of biomarker expressions that are associated with sleepingand/or tighten gastric band (306) when biomarker expressions that areassociated with sleeping are no longer detected. In addition or in thealternative, control module (302) may be configured to controlpump/reservoir system (307) to tighten gastric band (306) based on thedetection of biomarker expressions that are associated with the patientbeing awake and/or loosen gastric band (306) when biomarker expressionsthat are associated with the patient being awake are no longer detected.Again, such adjustments may be made in real time, in near-real time, orotherwise.

As still another merely illustrative example, it should be understoodthat a device like a gastric band (306) may be used to addressgastroesophageal reflux disease (GERD). For instance, such a band may beplaced at or near the bottom of a patient's esophagus, and may betightened to essentially close off the patient's esophagus during theoccurrence of acid reflux to reduce the likelihood of harm to thepatient's esophageal tissue that might otherwise occur from the acidreflux. Such a band may also be fluid actuated like gastric band (306),and may be coupled with an analog to pump/reservoir system (307).Accordingly, biomarker sensor (301) may be configured to detectbiomarkers associated with irritation (or other effects) to thepatient's esophageal tissue associated with acid reflux. In some suchversions control module (302) may be configured to control the analog ofpump/reservoir system (307) to tighten the band based on the detectionof biomarker expressions that are associated with acid reflux loosen theband when biomarker expressions that are associated with acid reflux areno longer detected. Again, such adjustments may be made in real time, innear-real time, or otherwise.

It should also be understood that a gastric band (306) (or band toaddress acid reflux or some other condition) need not be fluid actuated.For instance, fluid actuated gastric band (306) may be replaced with amechanically actuated gastric band as described in U.S. Pat. No.6,067,991, entitled “Mechanical Food Intake Restriction Device,” issuedMay 30, 2000, the disclosure of which is incorporated by referenceherein. Of course, with a version gastric band (306) that is not fluidactuated, pump/reservoir system (307) may be eliminated. In some suchversions, control module (302) may instead be coupled with a motor orwhatever other device drives the mechanically actuated version ofgastric band (306), and may selectively tighten or loosen such a gastricband (306) in accordance with the teachings herein. Again, suchadjustments may be made in real time, in near-real time, or otherwise.

2. Exemplary Presentation of Implant-Originated Feedback toPatient/Clinician Based on Biomarker Feedback

FIG. 13 shows another exemplary gastric band system (350). In thisexample, gastric band system (350) includes a biomarker sensor (301), acontrol module (302), an adjustable gastric band (306), and a feedbackdevice (308). In the present example, biomarker sensor (301), controlmodule (302), adjustable gastric band (306), and feedback device (308)are all implanted within a patient. Gastric band system (350) of thisexample provides feedback to the patient through feedback device (308),based at least in part on biomarker expressions detected by biomarkersensor (301). Biomarker sensor (301) is in communication with controlmodule (302), and is operable to communicate sensed biomarker data tocontrol module (302). Control module (302) is in communication withfeedback device (308), and is operable to control feedback device (308)based at least in part on biomarker data communicated from biomarkersensor (301). In this example, gastric band (306) is not coupled withany of biomarker sensor (301), control module (302), or feedback device(308). However, in some versions gastric band (306) may be coupled withany or all of these components, among other components.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may be configured in accordance with theteachings provided above in the context of surgical system (300).Control module (302) may also take a variety of forms. By way of exampleonly, control module (302) may be configured in accordance with theteachings provided above in the context of surgical system (300).Gastric band (306) may also take a variety of forms. By way of exampleonly, gastric band (306) may be configured in accordance with theteachings provided above in the context of gastric band system (340). Asmerely exemplary alternative, gastric band (306) may include animplanted injection port instead of pump/reservoir system (307), wherebythe amount of fluid in gastric band (306) (and hence, the degree ofrestriction created in the patient's stomach by gastric band (306)) isadjusted using a syringe with a needle inserted in the injection port.For instance, such an injection port may be constructed and operable inaccordance with the teachings of U.S. Pub. No. 2005/0283119, entitled“Implantable Medical Device with Reversible Attachment Mechanism andMethod,” published Dec. 22, 2005, the disclosure of which isincorporated by reference herein.

Feedback device (308) of the present example is implanted in the patientand may also take a variety of forms. In some versions, feedback device(308) is configured to provide haptic feedback to the patient. Forinstance, feedback device (308) may include a vibration generator (e.g.,similar to a vibration generator in a cell phone, etc.) that isconfigured to generate vibrations that can be felt by the patient.Feedback device (308) may thus provide the patient with notification ofone or more conditions as described in greater detail below. In additionor in the alternative, feedback device (308) may include a communicatorthat is configured to communicate an alert and/or other information to alocation external to the patient. For instance, such a communicator mayinclude a wire passing through the patient's skin to an external device,a coil implanted in the patient that is operable to telemetricallycommunicate data to a corresponding coil that is external to thepatient, or any other type of suitable communication device. Feedbackdevice (308) may thus provide another person or system with notificationof one or more conditions as described in greater detail below. In someversions, feedback device (308) is constructed in accordance with theteachings of U.S. patent app. Ser. No. 12/640,048, entitled “ImplantablePort with Vibratory Feedback,” filed Dec. 17, 2009, the disclosure ofwhich is incorporated by reference herein.

In some versions, control module (302) controls feedback device (308)based at least in part on biomarker data communicated from biomarkersensor (301); such as when biomarker data from biomarker sensor (301)exceeds or falls below one or more threshold values and/or when thebiomarker data otherwise meets some predefined criteria. For instance,biomarker sensor (301) may be configured to detect biomarkers associatedwith tissue irritation or other effects on tissue that may beundesirable and that may be caused by gastric band (306). In versionswhere feedback device (308) is configured to provide notification to thepatient, control module (302) may be configured to control feedbackdevice (308) to alert the patient to the need for gastric band (306) tobe adjusted. For instance, feedback device (308) may vibrate in responseto biomarker expressions that indicate the need for a gastric band (306)adjustment, and such vibrations may prompt the patient to contact theirphysician to obtain the adjustment. As another merely illustrativevariation, biomarker sensor (301) may be configured to detect biomarkerexpressions associated with failure of a gastric band (306) (e.g.,leakage of fluid from gastric band (306), etc.); and control module(302) may be configured to control feedback device (308) to alert thepatient to the need for such failure to be addressed.

As another merely illustrative example, in versions where feedbackdevice (308) is configured to communicate alerts or other information toan external location, feedback device (308) may also be used tocommunicate the need for an adjustment of gastric band (306). Forinstance, biomarker sensor (301) may be configured to detect biomarkersassociated with tissue irritation or other effects on tissue that may beundesirable and that may be caused by gastric band (306). Control module(302) may be configured to drive feedback device (308) to communicatethe need for an adjustment of gastric band (306) to an external device,in response to biomarker expressions that indicate the need for agastric band (306) adjustment. In some versions, such communicationsfrom feedback device (308) include actual biomarker data in addition toan indication that gastric band (306) needs to be adjusted. In someother versions, such communications from feedback device (308) justinclude an indication that gastric band (306) needs to be adjusted. Instill other versions, feedback device (308) simply communicatesbiomarker data when feedback device (308) is interrogated by an externaldevice (e.g., via transcutaneous wireless telemetry). Thus,communications from feedback device (308) need not only be prompted by adetermination from control module (302) that biomarker data as exceededor fallen below threshold levels or has otherwise met some predefinedcondition. In other words, an external device may instead make thedetermination that gastric band (306) needs to be adjusted.

In versions of feedback device (308) that provide wireless communicationto an external device, it should be understood that such wirelesscommunication may be provided in various ways. For instance, feedbackdevice (308) may be subject to interrogation by a coil placed adjacentto the patient's skin by a physician during a visit. By way of exampleonly, feedback device (308) may thus be configured and interrogated inaccordance with the teachings of U.S. Pub. No. 2006/0189888, entitled“Device for Non-Invasive Measurement of Fluid Pressure in an AdjustableRestriction Device,” published Aug. 24, 2006, the disclosure of which isincorporated by reference herein. As another merely illustrativeexample, the patient may be provided with a device that is wornexternally to the patient and that is in wireless communication withfeedback device (308). Such an external device may be configured andoperable in accordance with the teachings of U.S. Pub. No. 2006/0199997,entitled “Monitoring of a Food Intake Restriction Device,” publishedSep. 7, 2006, the disclosure of which is incorporated by referenceherein. Such an external device may thus receive alerts and/or biomarkerrelated data from feedback device (308), and may further communicatesuch alerts and/or data to a remote computer system and/or to aphysician, etc. It should be understood that, in some scenarios,biomarker related data to an external device may not necessarilyindicate the need for an adjustment to gastric band (306). For instance,such biomarker related data may be indicative of a patient's compliancewith a dietary plan and/or other biological conditions.

It should also be understood that the above-described systemarchitecture and operability of gastric band system (350) may be appliedto virtually any type of implanted device. For instance, to the extentthat another implanted device has adjustability and the need for anadjustment to the implant can be detected through biomarker expressions,an equivalent to feedback device (308) may be used to notify the patientand/or transmit notification to an external device when an adjustment isneeded. Likewise, to the extent that problems associated with anotherimplanted device can be detected through biomarker expressions, anequivalent to feedback device (308) may be used to notify the patientand/or transmit notification to an external device when a problem isdetected. Furthermore, in versions where the equivalent to feedbackdevice (308) is capable of communicating with an external device,feedback device (308) may also communicate more than just a notificationof a problem (e.g., biomarker data itself, an interpretation ofbiomarker data, etc.). Of course, data communicated from an equivalentof feedback device (308) to an external device need not be limited toproblems associated with an implanted device. For instance, anequivalent of feedback device (308) may communicate any other type ofbiological data detected through biomarker expressions, including butnot limited to biological data relating to effects of an implant orother biological data.

It is also contemplated that an alternative system may include abiomarker sensor (301), a control module (302), and a feedback device(308) without necessarily needing to include any other implanted device.In other words, gastric band (306) may be omitted from system (350), andno other implanted device needs to be provided in place of gastric band(306). It should be appreciated that such systems may be used to detectvirtually any type of medical condition and provide communication to thepatient, to an external device, to a physician, etc., via feedbackdevice (308). By way of example only, biomarker sensor (301) may beconfigured to detect biomarker expressions associated with infection(e.g., in a patient that has just undergone a surgical procedurepresenting an appreciable risk of infection); to detect biomarkerexpressions associated with a heart attack (e.g., in a patient that hasalready had a heart attack or is at a significantly high risk of a heartattack); to detect biomarker expressions associated with hypoglycemia(e.g., in a patient that has diabetes); to detect biomarker expressionsassociated with cancer (e.g., in a high-risk patient from whom canceroustumors or lesions have already been removed); or to detect biomarkerexpressions associated with various other medical/biological conditions.As in system (350) described above, control module (302) may commandfeedback device (308) when biomarker sensor (301) detects biomarkerexpressions associated with such medical/biological conditions. As alsoin system (350) described above, a feedback device (308) so commandedmay provide a haptic notification to the patient and/or may communicatethe presence of such medical/biological conditions to an external devicevia wire or wirelessly. Furthermore, like in system (350) describedabove, such information and/or notifications may be communicated in realtime, in near-real time, or in some other suitable fashion. Forinstance, storage module (302) may store such information and onlycommunicate it after feedback device (308) is interrogated by anexternal device.

3. Exemplary Automatic Adjustment of Drug Delivery by Drug InfusionSystem Based on Biomarker Feedback

As yet another merely illustrative example, FIG. 14 depicts an exemplarydrug infusion system (360) that includes a biomarker sensor (301), acontrol module (302), and a drug infusion device (309). In the presentexample, biomarker sensor (301), control module (302), and drug infusiondevice (309) are all implanted within a patient. Drug infusion system(360) of this example provides administration of drugs through druginfusion device (309) based at least in part on biomarker expressionsdetected by biomarker sensor (301). Biomarker sensor (301) is incommunication with control module (302), and is operable to communicatesensed biomarker data to control module (302). Control module (302) isin communication with pump/reservoir system (307), and is operable tocontrol drug infusion device (309) based at least in part on biomarkerdata communicated from biomarker sensor (301). While FIG. 14 showsbiomarker sensor (301), control module (302), and drug infusion device(309) as separate components, it should be understood that one or moreof these components may in fact be integrated into a single device. Thecomponents shown in FIG. 14 may also be provided in plural form. Itshould also be understood that communication between components may beprovided in various ways, including but not limited to wired, wireless,or combinations of wired and wireless.

Biomarker sensor (301) may take a variety of forms. By way of exampleonly, biomarker sensor (301) may be configured in accordance with theteachings provided above in the context of surgical system (300).Control module (302) may also take a variety of forms. By way of exampleonly, control module (302) may be configured in accordance with theteachings provided above in the context of surgical system (300). Druginfusion device (309) may comprise any suitable conventional ornon-conventional type of drug infusion device. In particular, druginfusion device (309) may include a drug or other type of agent, and maybe operable to administer that drug or agent to the patient in aregulated fashion. By way of example only, drug infusion device (309)may contain and administer vasoconstrictors, corticosteroids, NSAIDs,DNA, and/or any other suitable type of agent(s), drugs, and/or othersubstances. While the term “drug” is used in the phrase “drug infusiondevice (309)” it is contemplated that drug infusion device (309) maycontain and administer various types of substances (e.g., liquids, etc.)that might not necessarily fit within conventional understandings of theterm “drug.” Such substances may be administered for therapeutic orremedial purposes, for prophylactic or preventative purposes, and/or forany other suitable purpose(s).

In some versions, control module (302) controls drug infusion device(309) based at least in part on biomarker data communicated frombiomarker sensor (301); such as when biomarker data from biomarkersensor (301) exceeds or falls below one or more threshold values and/orwhen the biomarker data otherwise meets some predefined criteria. Forinstance, drug infusion device (309) may be implanted in a patient toaddress a particular medical/biological condition. Examples of suchconditions, as well as substances that may be administered by druginfusion device (309) to address such conditions, will be apparent tothose of ordinary skill in the art in view of the teachings herein. Inthe present example, biomarker sensor (301) is configured to detectbiomarker expressions that relate to the medical/biological conditionthat drug infusion device (309) is intended to address. Accordingly,control module (302) may be configured to regulate the administration ofa drug, agent, or other type of substance by drug infusion device (309),based at least in part on biomarker data obtained by biomarker sensor(301). For instance, control module (302) may increase or decrease thedosage provided to the patient by drug infusion device (309), based atleast in part on biomarker data obtained by biomarker sensor (301).

Drug infusion system (360) may also include an equivalent to feedbackdevice (308) as described above. For instance, in contexts where druginfusion device (309) is capable of having its administered substancereplenished from an external source (e.g., via injection), feedbackdevice (308) may be configured to communicate to the patient and/or toan external device a need for such substance to be replenished. Inaddition or in the alternative, feedback device (308) may be configuredto communicate to the patient and/or to an external device anotification that drug infusion device (309) is not working properly. Asyet another merely illustrative variation, feedback device (308) may beconfigured to communicate to the patient and/or to an external device anadverse reaction by the patient to a substance administered by druginfusion device (309). In addition or in the alternative, feedbackdevice (308) may be configured to communicate to the patient and/or toan external device any other medical/biological condition that is or isnot related to drug infusion device (309). In any of the foregoingexamples, information communicated by feedback device (308) may (or maynot) be based at least in part on biomarker expressions detected bybiomarker sensor (301).

As a merely illustrative example, a sensor device (301) could bedesigned to measure levels of melatonin. When control module (302)observes levels of melatonin below those of historical norms, controlmodule (302) could increase neurological stimulation provided by animplanted device (303) in order to achieve optimum levels of sedation.Still other ways in which feedback received through monitoring,analysis, or other processing of biomarkers as described herein may beused to automatically control or otherwise affect the operation of oneor more devices that are implanted within a patient, in real time orotherwise, will be apparent to those of ordinary skill in the art inview of the teachings herein. Similarly, other ways in which feedbackreceived through monitoring, analysis, or other processing of biomarkersas described herein may be used to detect undesirable conditions withina patient, regardless of whether such conditions are associated withanother implanted device, will be apparent to those of ordinary skill inthe art in view of the teachings herein. In addition, other ways inwhich biological conditions detected through the expressions ofbiomarkers (regardless of whether such biological conditions aredesirable or not) may be communicated to a patient and/or to otherpersons or systems, in real time or otherwise, will be apparent to thoseof ordinary skill in the art in view of the teachings herein.

D. Exemplary Devices for Administration of Agents Based on BiomarkerFeedback or Otherwise

As noted above with reference to block (60) of FIG. 1, therapies ortreatments may be selected and administered based at least in part onbiomarker related information. By way of example only, in someinstances, despite the cauterizing capabilities of electrosurgicaldevices, surgeons may be reluctant to use an electrosurgical device dueto the threat of undesired thermal injury that might be caused by somesuch devices. It may therefore be desirable to provide hemostaticcapabilities to a non-electrosurgical cutting device (e.g., a “cold”scalpel) or enhance the existing hemostatic capabilities of anon-electrosurgical cutting device (e.g., a harmonic scalpel). Suchhemostatic capabilities may be particularly desirable where biomarkerdata indicates that a patient has a high propensity to bleed and/or areduced propensity to clot, etc. Hemostatic capabilities may be providedor enhanced for a non-electrosurgical cutting device by providing thecutting device with the capability of dispensing hemostatic substances.For instance, an unenergized scalpel may be configured to dispense aclotting agent as a mist, flood, or attached flow at the surgical siteas the scalpel is being used to cut (and/or after a cut is made with thescalpel). Similarly, a harmonic device may be configured to dispense anaerosol of a clotting agent, which may be dispersed by the vibratorymotion of the blade of the harmonic device as the harmonic blade isbeing used to cut (and/or after a cut is made with the harmonic blade).In addition to or in lieu of clotting agents, vasoconstrictive materialsmay be employed to give temporary hemostasis that resolves in such atime frame as to enable unimpeded blood flow to healing tissues. Ofcourse, various other types of agents or substances may be administeredby a medical device.

The below examples are provided mainly in the context of administeringgene therapies in response to biomarker related information as describedelsewhere herein (e.g., in accordance with block (60) of FIG. 1). Itshould be understood, however, that the below teachings may be readilyapplied to the administration of any other suitable type of therapy ortreatment, including but not limited to non-gene therapies ortreatments. Various examples of therapies or treatments that may beprovided are described elsewhere herein, while still other examples willbe apparent to those of ordinary skill in the art in view of theteachings herein. It should also be understood that, while the belowteachings are provided in the context of administering therapies ortreatments in response to biomarker related information, the belowteachings may also be readily applied to the administration of therapiesor treatments in response to other information (e.g., from conventionaldiagnostic techniques) in addition to or in the absence of biomarkerrelated information. In other words, the below teachings are notnecessarily limited to the administration of therapies or treatments inresponse to biomarker related information, as the below teachings may bereadily applied to the broader context of administering therapies ortreatments in general (e.g., without biomarker related information).

To the extent that therapies or treatments provided in accordance withthe below teachings are based on biomarker related information, suchbiomarker related information may be collected based on the teachings ofsection V.A. above, based on other teachings herein, and/or based on anyother suitable biomarker information collectiontechniques/devices/systems as will be apparent to those of ordinaryskill in the art in view of the teachings herein. Thus, it should beunderstood that in some versions, a single harmonic device may be usedto both obtain biomarker data as described above in section V.A. andadminister a gene therapy (or other form of therapy/treatment/etc.) asdescribed below, based at least in part on such biomarker data, and inreal time or near-real time. Furthermore, it should be understood thatany of the teachings below may be readily combined with any of theteachings provided above in section V.B.2. and/or with any otherteachings herein.

The following examples are also provided in the context of a harmonicsurgical instrument. It should be understood that, in some versions,harmonic surgical instruments may provide sonoporation capabilities thatfacilitate gene therapy without the use of viral carriers. In someinstances, sonoporation may be used to porate cell nuclei in the patientin addition to porating cell walls in the patient. In addition,transfection rates for gene therapies provided in accordance with thebelow teachings may be improved by putting the therapeutic DNA/genes ina fat cell (lipid) emulsion. By way of example only, the devices andtechniques described below may be provided in accordance with theteachings in Lin et al., “Sonoporation-Mediated Gene Transfer into AdultRat Dorsal Root Ganglion Cells,” Journal of Biomedical Science 17:44(2010), the disclosure of which is incorporated by reference herein. Asanother merely illustrative example, the devices and techniquesdescribed below may be provided in accordance with the teachings inNegishi, et al., “Delivery of an Angiogenic Gene into Ischemic Muscle byNovel Bubble Liposomes Followed by Ultrasound Exposure,” Pharm. Res.,DOI 10.1007/s11095-010-0286-4 (2010), the disclosure of which isincorporated by reference herein. As yet another merely illustrativeexample, the devices and techniques described below may be provided inaccordance with the teachings in Taniyama, et al., “Development of Safeand Efficient Novel Nonviral Gene Transfer Using Ultrasound: Enhancementof Transfection Efficiency of Naked Plasmid DNA in Skeletal Muscle,”Gene Therapy 9, 372-380 (2002), the disclosure of which is incorporatedby reference herein. As still another merely illustrative example, thedevices and techniques described below may be provided in accordancewith the teachings in Liang, et al., “Optimisation ofUltrasound-Mediated Gene Transfer (Sonoporation) in Skeletal MuscleCells” Ultrasound in Med. & Biol., Vol. 30, No. 11, pp. 1523-1529(2004), the disclosure of which is incorporated by reference herein.Various other suitable ways in which the below teachings may be carriedout will be apparent to those of ordinary skill in the art in view ofthe teachings herein.

By way of example only, the teachings below may be readily applied to aharmonic surgical instrument as shown and described in U.S. Pub. No.2006/0079874; a harmonic surgical instrument as shown and described inU.S. Pub. No. 207/0191713; a harmonic surgical instrument as shown anddescribed in U.S. Pub. No. 2007/0282333; and/or a harmonic surgicalinstrument as shown and described in U.S. Pub. No. 2008/0200940. Asanother merely illustrative example, the teachings below may be readilyapplied to device (100) described above or to harmonic surgicalinstrument (210) described above. Still other suitable types of harmonicsurgical instruments to which the below teachings may be readily appliedwill be apparent to those of ordinary skill in the art in view of theteachings herein. It should also be understood that, in some versions ofthe examples provided below, the devices are configured such that thetherapeutic agents are only dispensed when the harmonic blade is active.In some instances, this might reduce unnecessary waste of therapeuticagent.

It is also contemplated that the below teachings may be readily appliedto various other kinds of medical devices, including but not limited tosurgical instruments, medical implants, etc. For instance, the belowteachings may be readily applied to virtually any of the kinds ofmedical devices that are referred to herein. Still other suitabledevices to which the below teachings may be readily applied will beapparent to those of ordinary skill in the art in view of the teachingsherein. It should therefore be understood that the below examplesinclude harmonic surgical instruments by way of illustration only, andthat the below teachings are not intended to be limited to just harmonicsurgical instruments. In some instances where gene therapies areadministered through a non-harmonic medical device, it may be necessaryto provide such gene therapy through a viral carrier. It should also beunderstood that various components, features, and operabilities of thebelow examples may be readily combined with each other in various ways,as will be apparent to those of ordinary skill in the art in view of theteachings herein.

1. Exemplary Dispensation of Therapeutic Agent from Blade of HarmonicDevice

The following examples include various harmonic surgical instrument endeffectors that are operable to dispense a therapeutic agent (e.g., genetherapy fluid, etc.) through a harmonic blade. In each of theseexamples, it should be understood that the openings through which thetherapeutic agent is delivered may be located at positions correspondingto nodes of the ultrasonic energy being transmitted through the harmonicblade. In some instances, dispensing the therapeutic agent at positionscorresponding to nodes may reduce the likelihood that the ultrasonicenergy has an adverse effect on the therapeutic agent itself. In someother instances, the ultrasonic energy may have no adverse effect on thetherapeutic agent itself regardless of where the therapeutic agent isadministered along the length of the harmonic blade.

FIG. 15 depicts an exemplary end effector (400) that may be provided ona harmonic surgical instrument to deliver a therapeutic agent (e.g.,gene therapy fluid, etc.) at a surgical site or other wound site. Itshould be understood that end effector (400) may be provided on anyharmonic surgical instrument referred to herein, among other types ofsurgical instruments. As shown, end effector (400) is provided at thedistal end of a shaft (402), and includes a clamp pad (404) and aharmonic blade (406). Clamp pad (404) is coupled with a pair of actuatorarms (408), which are slidably disposed within shaft (402) andselectively translate to pivot clamp pad (404) relative to harmonicblade (406). A waveguide (410) also extends through shaft (402) and isconfigured to transmit ultrasonic energy from an ultrasonic transducerto harmonic blade (406).

Harmonic blade (406) of the present example also includes a pair ofopenings (412) formed in its side. While two openings (412) are shown,it should be understood that any other suitable number of openings (412)may be used and that openings (412) may be located at any suitablepositions along the length of harmonic blade (406). A conduit (414) isin fluid communication with openings (412). Conduit (414) extendsthrough shaft (402) adjacent to actuator arms (408) and waveguide (410).In an exemplary use, a therapeutic agent (416) is dispensed at asurgical site or other wound site via openings (412). Examples ofvarious suitable structures that may be coupled with conduit (414) tocommunicate therapeutic agent (416) to openings (412) will be describedbelow in section V.D.3., while other examples will be apparent to thoseof ordinary skill in the art in view of the teachings herein. As notedabove, sonoporation provided by harmonic blade (406) may facilitatetransfection in instances where therapeutic agent (416) comprisesDNA/genes. Thus, in some examples, therapeutic agent (416) isadministered when harmonic blade (406) is actively oscillating. Itshould also be understood that an oscillating harmonic blade (406) mayaerosolize therapeutic agent (416) as therapeutic agent (416) isdispensed through openings (412).

FIG. 16 depicts another exemplary end effector (430) that may beprovided on a harmonic surgical instrument to deliver a therapeuticagent (e.g., gene therapy fluid, etc.) at a surgical site or other woundsite. It should be understood that end effector (430) may be provided onany harmonic surgical instrument referred to herein, among other typesof surgical instruments. As shown, end effector (430) is provided at thedistal end of a shaft (432), and includes a clamp pad (434) and aharmonic blade (436). Clamp pad (434) is coupled with a pair of actuatorarms (438), which are slidably disposed within shaft (432) andselectively translate to pivot clamp pad (434) relative to harmonicblade (436). A waveguide (440) also extends through shaft (432) and isconfigured to transmit ultrasonic energy from an ultrasonic transducerto harmonic blade (436).

Harmonic blade (436) of the present example also includes a pair ofopenings (442) formed in its side. While two openings (442) are shown,it should be understood that any other suitable number of openings (442)may be used and that openings (442) may be located at any suitablepositions along the length of harmonic blade (436). A lumen (444) is influid communication with openings (412). Lumen (444) is formed throughwaveguide (440) and harmonic blade (436). End effector (430) of thisexample is thus similar to end effector (400) of FIG. 15, except thatend effector (430) has lumen (444) instead of having a separate conduit(414). In an exemplary use, a therapeutic agent (446) is dispensed at asurgical site or other wound site via openings (442). Examples ofvarious suitable structures that may be coupled with lumen (444) tocommunicate therapeutic agent (446) to openings (442) will be describedbelow in section V.D.3., while other examples will be apparent to thoseof ordinary skill in the art in view of the teachings herein. As notedabove, sonoporation provided by harmonic blade (436) may facilitatetransfection in instances where therapeutic agent (446) comprisesDNA/genes. Thus, in some examples, therapeutic agent (446) isadministered when harmonic blade (436) is actively oscillating. Itshould also be understood that an oscillating harmonic blade (436) mayaerosolize therapeutic agent (446) as therapeutic agent (446) isdispensed through openings (442).

FIG. 17 depicts another exemplary end effector (460) that may beprovided on a harmonic surgical instrument to deliver a therapeuticagent (e.g., gene therapy fluid, etc.) at a surgical site or other woundsite. It should be understood that end effector (460) may be provided onany harmonic surgical instrument referred to herein, among other typesof surgical instruments. As shown, end effector (460) is provided at thedistal end of a shaft (462), and includes a clamp pad (464) and aharmonic blade (466). Clamp pad (464) is coupled with a pair of actuatorarms (468), which are slidably disposed within shaft (462) andselectively translate to pivot clamp pad (464) relative to harmonicblade (466). A waveguide (not shown) also extends through shaft (462)and is configured to transmit ultrasonic energy from an ultrasonictransducer to harmonic blade (466).

Harmonic blade (466) of the present example also includes a recessedchannel (468) formed in its side and a recessed pool (470) at the distalend of channel (468). While pool (470) is shown at approximately themid-point along the length of harmonic blade (466), it should beunderstood that pool (470) may be located at any other suitable positionalong the length of harmonic blade (466). The proximal end of channel(468) may be in fluid communication with a conduit (e.g., similar toconduit (414) described above), with an internal lumen formed in thewaveguide and/or in harmonic blade (466) (e.g., similar to lumen (444)described above), or with any other suitable structure configured tocommunicate fluid to channel (468). In an exemplary use, a therapeuticagent (472) is dispensed at a surgical site or other wound site via pool(470). In particular, FIG. 18A shows harmonic blade (466) in anon-activated state while FIG. 18B shows harmonic blade (466) in anactivated state. When harmonic blade (466) is in a non-activated stateas shown in FIG. 18A, therapeutic agent (472) wicks down channel (468)and pools up in pool (470). When harmonic blade (466) is activated asshown in FIG. 18B, the oscillating action of harmonic blade (466) throwstherapeutic agent (472) from pool (470). It should be understood thattherapeutic agent (472) may continue to wick down channel (468) and bethrown from pool (470) while harmonic blade (466) remains activated. Itshould also be understood that an activated harmonic blade (466) mayalso aerosolize therapeutic agent (472). Examples of various suitablestructures that may be coupled with channel (468) to communicatetherapeutic agent (472) to pool (470) will be described below in sectionV.D.3., while other examples will be apparent to those of ordinary skillin the art in view of the teachings herein. It should also be understoodthat, as noted above, sonoporation provided by harmonic blade (466) mayfacilitate transfection in instances where therapeutic agent (472)comprises DNA/genes.

FIGS. 19A-C and 20 show an exemplary harmonic blade (500) that may beincorporated into an end effector of a harmonic surgical instrument todeliver a therapeutic agent (e.g., gene therapy fluid, etc.) at asurgical site or other wound site. It should be understood that harmonicblade (500) may be provided on any harmonic surgical instrument referredto herein, among other types of surgical instruments. Harmonic blade(500) of the present example includes a recessed channel (510) formed inits side. While channel (510) is shown as being formed in only one sideof harmonic blade (500), it should be understood that more than one sideof harmonic blade (500) may include a channel (510). Channel (510) ofthis example includes a plurality of pocket regions (512) that aredefined in part by fingers (514), which create narrow regions (516) inchannel (510). Each finger (514) includes a distally-inclined distalface (518) and a distally inclined proximal face (520). Thedistally-inclined orientations of faces (518, 520) are configured tofacilitate distal communication of therapeutic agent (522) along channel(510). This action may be seen by viewing FIGS. 19A-19C as a serieswhere harmonic blade (500) is activated.

FIG. 19A shows harmonic blade (500) at a distal position at a first timeinstant during activation. At this stage, therapeutic agent (522) hasreached the fifth pocket region (512) from the distal end (502) ofharmonic blade (500). In FIG. 19B, harmonic blade (500) has movedproximally during oscillation at a second time instant, as indicated byarrow (524). The inertia of therapeutic agent (522) has kept theposition of therapeutic agent (522) constant relative to the externalenvironment, yet the proximal movement of harmonic blade (500) haseffectively “advanced” therapeutic agent (522) to the fourth pocketregion (512) from distal end (502) of harmonic blade (500). Thedistally-inclined orientation of proximal face (520) also substantiallyprevents finger (514) from pushing therapeutic agent (522) proximally asharmonic blade (500) moves proximally, allowing therapeutic agent (522)to essentially “ride over” finger (514) as harmonic blade (500) movesproximally. In FIG. 19C, harmonic blade (500) has moved distally duringoscillation at a third time instant, as indicated by arrow (526). Thedistally-inclined orientation of distal face (518) has allowed finger(514) to throw therapeutic agent (522) distally to the third pocketregion (512) from distal end (502) of harmonic blade (500), as indicatedby arrow (528). As harmonic blade (500) continues to oscillate, thisdistal progression of therapeutic agent (522) continues. Any therapeuticagent (522) that makes it to the distal-most pocket region (512) will bethrown out laterally from harmonic blade (500). Of course, at least sometherapeutic agent (522) may be thrown laterally from harmonic blade(500) before it ever reaches the distal-most pocket region (512). Itshould also be understood that pressure from the source of therapeuticagent (522) may facilitate distal communication of therapeutic agent(522) along channel (510). Furthermore, it should be understood that anoscillating harmonic blade (500) may aerosolize therapeutic agent (522)as therapeutic agent (522) is thrown from harmonic blade (500).

Examples of various suitable structures that may be coupled with channel(510) to communicate therapeutic agent (522) to harmonic blade (500)will be described below in section V.D.3., while other examples will beapparent to those of ordinary skill in the art in view of the teachingsherein. It should also be understood that, as noted above, sonoporationprovided by harmonic blade (500) may facilitate transfection ininstances where therapeutic agent (522) comprises DNA/genes.

FIG. 21 shows another exemplary harmonic blade (530) that may beincorporated into an end effector of a harmonic surgical instrument todeliver a therapeutic agent (e.g., gene therapy fluid, etc.) at asurgical site or other wound site. It should be understood that harmonicblade (530) may be provided on any harmonic surgical instrument referredto herein, among other types of surgical instruments. Harmonic blade(530) of the present example includes a pair of recessed channels (540)formed in its sides. Recessed channels (540) each include several spacedapart and outwardly extending spikes (544) along the length of eachchannel (540). In some versions, spikes (544) are configured to assistin conveying therapeutic agent (546) distally along the length ofharmonic blade (530) as harmonic blade (530) oscillates. In addition orin the alternative, spikes (544) may be configured to assist in throwingtherapeutic agent (546) from harmonic blade (530) as harmonic blade(530) oscillates. Various suitable configurations and spacings that maybe used for channels (540) and spikes (544) will be apparent to those ofordinary skill in the art in view of the teachings herein. By way ofexample only, spikes (544) may alternatively be formed as roundedprotrusions instead of having sharp points as shown. Furthermore, itshould be understood that an oscillating harmonic blade (530) mayaerosolize therapeutic agent (546) as therapeutic agent (546) is thrownfrom harmonic blade (530). Examples of various suitable structures thatmay be coupled with channels (540) to communicate therapeutic agent(546) to harmonic blade (530) will be described below in section V.D.3.,while other examples will be apparent to those of ordinary skill in theart in view of the teachings herein.

FIG. 22 shows another exemplary harmonic blade (550) that may beincorporated into an end effector of a harmonic surgical instrument todeliver a therapeutic agent (e.g., gene therapy fluid, etc.) at asurgical site or other wound site. It should be understood that harmonicblade (550) may be provided on any harmonic surgical instrument referredto herein, among other types of surgical instruments. Harmonic blade(550) of the present example includes a recessed channel (560) formedalong one of its longitudinally extending edge corners. While harmonicblade (550) is shown with channel (560) extending along only one edgecorner, it should be understood that one or more additionallongitudinally extending edge corners of harmonic blade (550) mayinclude a channel (560). Recessed channel (560) includes several spacedapart and outwardly extending spikes (564) along the length of channel(560). In some versions, spikes (564) are configured to assist inconveying therapeutic agent (566) distally along the length of harmonicblade (550) as harmonic blade (550) oscillates. In addition or in thealternative, spikes (564) may be configured to assist in throwingtherapeutic agent (566) from harmonic blade (550) as harmonic blade(550) oscillates. Various suitable configurations and spacings that maybe used for channel (550) and spikes (564) will be apparent to those ofordinary skill in the art in view of the teachings herein. By way ofexample only, spikes (564) may alternatively be formed as roundedprotrusions instead of having sharp points as shown. Furthermore, itshould be understood that an oscillating harmonic blade (550) mayaerosolize therapeutic agent (566) as therapeutic agent (566) is thrownfrom harmonic blade (550). Examples of various suitable structures thatmay be coupled with channel (560) to communicate therapeutic agent (566)to harmonic blade (550) will be described below in section V.D.3., whileother examples will be apparent to those of ordinary skill in the art inview of the teachings herein.

FIGS. 23A-B show another exemplary harmonic blade (570) that may beincorporated into an end effector of a harmonic surgical instrument todeliver a therapeutic agent (e.g., gene therapy fluid, etc.) at asurgical site or other wound site. It should be understood that harmonicblade (570) may be provided on any harmonic surgical instrument referredto herein, among other types of surgical instruments. A sheath (580) isdisposed about a proximal portion of harmonic blade (570) in the presentexample. The inner diameter of sheath (580) is sufficiently greater thanthe outer diameter of harmonic blade (570) to allow therapeutic agent(584) to be communicated therebetween. Harmonic blade (570) includes aplurality of annular recesses (572) along the portion of harmonic blade(570) that is disposed in sheath (580). A plurality of seals (582) arelocated within sheath (582) and correspond with the longitudinalpositions of annular recesses (572). Seals (582) define an innerdiameter that is greater than the outer diameter of annular recesses(572) yet that is less than the outer diameter of the rest of harmonicblade (570). Thus, when harmonic blade (570) is at a proximal positionduring oscillation or before oscillation as shown in FIG. 23A,therapeutic agent (584) is trapped between seals (582) and behind seals(582).

When harmonic blade (570) is at a distal position during oscillation asshown in FIG. 23B, the gap (586) provided between seals (582) andannular recesses (572) permit distal passage of therapeutic agent (584)out through the open distal end (588) of sheath (580). In some versions,therapeutic agent (584) exits through open distal end (588) in a pulsedfashion (e.g., only exiting when harmonic blade (570) is at the distalposition during oscillation, etc.). Distal communication of therapeuticagent (584) through sheath (580) may be provided by oscillation ofharmonic blade (570) and/or by pressure from the source of therapeuticagent (584). Examples of various suitable structures that may be coupledwith sheath (580) to communicate therapeutic agent (584) through sheath(580) will be described below in section V.D.3., while other exampleswill be apparent to those of ordinary skill in the art in view of theteachings herein. It should also be understood that therapeutic agent(584) may be leaked out, be pushed out, and/or be aerosolized as itexits open distal end (588) of sheath (580).

FIGS. 24A-B show another exemplary harmonic blade (600) that may beincorporated into an end effector of a harmonic surgical instrument todeliver a therapeutic agent (e.g., gene therapy fluid, etc.) at asurgical site or other wound site. It should be understood that harmonicblade (600) may be provided on any harmonic surgical instrument referredto herein, among other types of surgical instruments. A sheath (620) isdisposed about a proximal portion of harmonic blade (600) in the presentexample. The inner diameter of sheath (620) is sufficiently greater thanthe outer diameter of harmonic blade (600) to allow therapeutic agent(644) to be communicated therebetween. Harmonic blade (600) includes anoutwardly extending annular protrusion (602) that corresponds with aninwardly extending annular flange (622) of sheath (620). In particular,when harmonic blade (600) is at a distal position during oscillation orbefore oscillation as shown in FIG. 24A, therapeutic agent (644) istrapped behind annular flange (622).

When harmonic blade (600) is at a proximal position during oscillationas shown in FIG. 24B, a gap (624) is opened up between harmonic blade(600) and annular flange (622), permitting exit of therapeutic agent(644) therebetween. In some versions, therapeutic agent (644) exitsthrough gap (624) in a pulsed fashion (e.g., only exiting when harmonicblade (600) is at the distal position during oscillation, etc.). Distalcommunication of therapeutic agent (644) through sheath (620) may beprovided by oscillation of harmonic blade (600) and/or by pressure fromthe source of therapeutic agent (644). Examples of various suitablestructures that may be coupled with sheath (620) to communicatetherapeutic agent (644) through sheath (620) will be described below insection V.D.3., while other examples will be apparent to those ofordinary skill in the art in view of the teachings herein. It shouldalso be understood that therapeutic agent (644) may be leaked out, bepushed out, and/or be aerosolized as it exits gap (624).

FIG. 25 depicts another exemplary end effector (650) that may beprovided on a harmonic surgical instrument to deliver a therapeuticagent (e.g., gene therapy fluid, etc.) at a surgical site or other woundsite. It should be understood that end effector (650) may be provided onany harmonic surgical instrument referred to herein, among other typesof surgical instruments. As shown, end effector (650) includes a clamppad (652) and a harmonic blade (654). A waveguide (656) extendsproximally from harmonic blade (654) and is configured to transmitultrasonic energy from an ultrasonic transducer to harmonic blade (654).An arm (660) extends proximally from clamp pad (652) and is operable topivot clamp pad (652) relative to harmonic blade (654). A wicking mesh(670) is also coupled with arm (660) and is wrapped about a proximalportion of harmonic blade (654). Wicking mesh (670) is flexible suchthat pivotal movement of arm (660) and clamp pad (652) relative toharmonic blade (654) will not adversely compromise the integrity ofwicking mesh (670). Wicking mesh (670) is configured to leak therapeuticagent (680) onto harmonic blade (654) as will be described in greaterdetail below, allowing therapeutic agent (680) to reach a surgical siteor other wound site.

An internal lumen (662) is defined in arm (660) and is in fluidcommunication with wicking mesh (670), such that wicking mesh (670) isconfigured to wick therapeutic agent (680) from internal lumen (662).Internal lumen (662) is also in fluid communication with a source oftherapeutic agent (680). In some versions, the source comprises atherapeutic agent cartridge that is inserted in arm (660). Additionalexamples of various suitable structures that may be coupled with lumen(662) to communicate therapeutic agent (680) to wicking mesh (670) willbe described below in section V.D.3., while other examples will beapparent to those of ordinary skill in the art in view of the teachingsherein. As noted above, sonoporation provided by harmonic blade (654)may facilitate transfection in instances where therapeutic agent (680)comprises DNA/genes. Thus, in some examples, therapeutic agent (680) isadministered when harmonic blade (654) is actively oscillating. Itshould also be understood that an oscillating harmonic blade (654) mayaerosolize therapeutic agent (680) as therapeutic agent (680) is leakedfrom wicking mesh (670) onto harmonic blade (654). Still other suitableways in which a therapeutic agent may be administered from a harmonicblade will be apparent to those of ordinary skill in the art in view ofthe teachings herein.

2. Exemplary Dispensation of Therapeutic Agent from Clamp Pad ofHarmonic Device

FIG. 26 depicts an exemplary end effector (700) that may be provided ona harmonic surgical instrument to deliver a therapeutic agent (e.g.,gene therapy fluid, etc.) at a surgical site or other wound site. Itshould be understood that end effector (700) may be provided on anyharmonic surgical instrument referred to herein, among other types ofsurgical instruments. As shown, end effector (700) is provided at thedistal end of a shaft (702), and includes a clamp pad (710) and aharmonic blade (704). Clamp pad (710) is operable to pivot relative toharmonic blade (704). A waveguide (706) extends through shaft (702) andis configured to transmit ultrasonic energy from an ultrasonictransducer to harmonic blade (704).

Clamp pad (710) of the present example includes a plurality of orifices(712). Orifices (712) are in fluid communication with a conduit (720),which extends through shaft (702) and is configured to communicatetherapeutic agent (724) to orifices (712). Examples of various suitablestructures that may be coupled with conduit (720) to communicatetherapeutic agent (724) to orifices (712) will be described below insection V.D.3., while other examples will be apparent to those ofordinary skill in the art in view of the teachings herein. In thepresent example, orifices (712) are subject to selective activation. Inparticular, as shown in FIG. 27A, a given orifice (712) is at leastsubstantially closed (712) when orifice (712) is in an inactive state.In some versions, orifice (712) is completely closed when inactive. Insome other versions, orifice (712) is not closed all the way wheninactive but is closed enough to prevent communication of therapeuticagent (724) through orifice (712). As shown in FIG. 27B, orifice (712)is opened when activated by a signal applied via wire (730). When soopened, orifice (712) permits communication of therapeutic agent (724)therethrough. Orifices (712) of this example are thus operable in amanner similar to those found in inkjet printer cartridges (e.g.,thermal inkjets or piezoelectric inkjets). As shown in FIG. 26, wire(730) also extends through shaft (702) to a switch or control module ofthe harmonic surgical instrument.

In some versions, a single wire (730) is used to selectively activateall orifices (712) in clamp pad (710) substantially simultaneously. Insome other versions, orifices (712) may be selectively activatedindividually or in groups. Such capabilities may allow the user (orautomated control system) to selectively adjust the dosage oftherapeutic agent (724). For instance, in situations calling for a highdosage of therapeutic agent (724), a relatively large group of orifices(712) or all orifices (712) may be activated to open; while insituations calling for a relatively low dosage of therapeutic agent(724), a relatively small group of orifices (712) even just a singleorifice (712) may be activated to open. In versions where orifices (712)are addressable in groups or independently from each other, a pluralityof wires (730) may be used, each being dedicated to a particularrespective orifice (712) or respective orifice group (712).Alternatively, using hardware and/or communication techniques/protocolsthat will be apparent to those of ordinary skill in the art in view ofthe teachings herein, a single wire (730) may still be used tocommunicate signals in versions where orifices (712) are addressable ingroups or independently from each other. In still other versions of endeffector (700), orifices (712) are simple openings that are not subjectto activation, such that the size of orifices (712) remainssubstantially constant, such that therapeutic agent (724) may simplyleak out or be forced out through orifices (712), and such that wire(730) may be eliminated.

As noted above, sonoporation provided by harmonic blade (704) mayfacilitate transfection in instances where therapeutic agent (724)comprises DNA/genes. Thus, in some examples, therapeutic agent (724) isadministered when harmonic blade (704) is actively oscillating. To thatend, orifices (712) may be selectively activated to only open (as shownin FIG. 27B) when harmonic blade (704) is activated; and tosubstantially close up (as shown in FIG. 27A) when harmonic blade (704)is inactive. For instance, orifices (712) may be tied to the samecontrol feature(s) (e.g., buttons) that is/are used to selectivelyactivate harmonic blade (704). Alternatively, orifices (712) may beoperable for activation independent from activation of harmonic blade(704). It should be understood that sonoporation provided by harmonicblade (704) may still facilitate transfection in instances wheretherapeutic agent (724) is introduced to the surgical site or other kindof wound site before harmonic blade (704) is activated, such that theintroduction of therapeutic agent (724) and the activation of harmonicblade (704) do not necessarily have to be synchronized in everyinstance.

FIG. 28 depicts another exemplary end effector (740) that may beprovided on a harmonic surgical instrument to deliver a therapeuticagent (e.g., gene therapy fluid, etc.) at a surgical site or other woundsite. It should be understood that end effector (740) may be provided onany harmonic surgical instrument referred to herein, among other typesof surgical instruments. As shown, end effector (740) is provided at thedistal end of a shaft (742), and includes a clamp pad (750) and aharmonic blade (744). Clamp pad (750) is operable to pivot relative toharmonic blade (744). A waveguide (746) extends through shaft (742) andis configured to transmit ultrasonic energy from an ultrasonictransducer to harmonic blade (744).

Clamp pad (750) of the present example includes a plurality of orifices(752). Clamp pad (750) also includes a chamber (754) to receive atherapeutic agent cartridge (760). Chamber (754) is configured suchthat, once therapeutic agent cartridge (760) is inserted in chamber(754), therapeutic agent (762) may be communicated through orifices(752). For instance, a sharp hollow nib (not shown) in chamber (754) maypierce a septum of cartridge (760) as soon as cartridge (760) is fullyinserted in chamber (754), and this hollow nib may be in fluidcommunication with orifices (752), such that the nib (and any othersuitable fluid communication components) provides a fluid circuit fromthe interior of cartridge (760) to orifices (752). In some versions,orifices (752) are subject to selective activation like orifices (712)described above. In some other versions, orifices (752) are simpleopenings that are not subject to activation, such that the size oforifices (752) remains substantially constant, such that therapeuticagent (762) may simply leak out or be forced out through orifices (752).It should therefore be understood that end effector (740) of thisexample may be configured and operable in a manner substantially similarto those described above with respect to end effector (700), with theexception that orifices (752) in end effector (740) receive therapeuticagent (762) from cartridge (760) instead of conduit (720).

FIG. 29 depicts yet another exemplary end effector (770) that may beprovided on a harmonic surgical instrument to deliver a therapeuticagent (e.g., gene therapy fluid, etc.) at a surgical site or other woundsite. It should be understood that end effector (770) may be provided onany harmonic surgical instrument referred to herein, among other typesof surgical instruments. As shown, end effector (770) is provided at thedistal end of a shaft (772), and includes a clamp pad (780) and aharmonic blade (774). Clamp pad (780) is operable to pivot relative toharmonic blade (774). A waveguide (not shown) extends through shaft(772) and is configured to transmit ultrasonic energy from an ultrasonictransducer to harmonic blade (774).

Clamp pad (780) of the present example includes a plurality of openings(782). Each opening (782) is associated with a respective therapeuticagent administration cell (784) in this example. As shown in FIG. 30,each cell (784) includes a reservoir (785) and a heat plate (786) thatheats up in response to an appropriate signal. To that end, each plate(786) may have a corresponding wire (788) or other structure forreceiving a signal. As shown in cell (784 a), the reservoir (785) ofeach cell (784) may be filled with therapeutic agent (789). Forinstance, therapeutic agent (789) may be communicated to each reservoir(785) via a conduit and/or the various structures described below insection V.D.3. and/or in any other suitable fashion. As shown in cell(784 b), heating of heat plate (786) by a signal applied through wire(788) causes therapeutic agent (789) to expand and ultimately blow outthrough opening (782) as shown in cell (784 c).

As noted above, sonoporation provided by harmonic blade (774) mayfacilitate transfection in instances where therapeutic agent (789)comprises DNA/genes. Thus, in some examples, therapeutic agent (789) isadministered when harmonic blade (774) is actively oscillating. To thatend, cells (784) may be selectively activated to expel therapeutic agent(789) only when harmonic blade (774) is activated. For instance, cells(784) may be tied to the same control feature(s) (e.g., buttons) thatis/are used to selectively activate harmonic blade (774). Alternatively,cells (784) may be operable for activation independent from activationof harmonic blade (704). It should also be understood that clamp pad(780) may be configured such that all cells (784) in clamp pad (780) areactivated simultaneously to expel therapeutic agent (789).Alternatively, clamp pad (780) may be configured such that cells (784)in clamp pad (780) may be activated individually or in groups to expeltherapeutic agent (789).

FIG. 31 shows an exemplary alternative type of agent administration cell(790) that may be readily incorporated into clamp pad (780) in additionto or in lieu of using agent administration cells (784) described above.In this example, each cell (790) includes a reservoir (792). Eachreservoir (792) is in fluid communication with a respective opening(794). In addition, a piezo stack (796) is provided in each reservoir(792). Each piezo stack (796) is configured to expand in response to anappropriate signal, thereby reducing the effective size of itscorresponding reservoir (792). As shown in cell (790 a), the reservoir(792) of each cell (790) may be filled with therapeutic agent (798). Forinstance, therapeutic agent (798) may be communicated to each reservoir(792) via a conduit and/or the various structures described below insection V.D.3. and/or in any other suitable fashion until the reservoir(792) is full as shown in cell (790 b). As shown in cell (790 c),application of an appropriate signal to piezo stack (796) causes peiozostack (796) to expand and expel therapeutic agent (798) through opening(794). Still other suitable ways in which a therapeutic agent may beadministered from cells will be apparent to those of ordinary skill inthe art in view of the teachings herein. Similarly, other suitable waysin which a therapeutic agent may be administered from a clamp pad willbe apparent to those of ordinary skill in the art in view of theteachings herein.

3. Exemplary Structures for Communicating Therapeutic Agent to EndEffector of Surgical Device

The examples described below relate to various structures and methodsthat may be used to provide communication of a therapeutic agent to theend effector of a surgical device. By way of example only, the belowteachings may be readily incorporated with any of the teachings providedin sections V.B.2, V.D.1, and/or V.D.2, above. Still other settings inwhich the below teachings may be readily applied will be apparent tothose of ordinary skill in the art in view of the teachings herein. Forinstance, while the following examples are provided in the context ofharmonic surgical instruments, it should be understood that thefollowing teachings may be readily applied to various other kinds ofsurgical instruments, other kinds of medical devices, etc. It shouldalso be understood that various components, features, and operabilitiesof the below examples may be readily combined with each other in variousways, as will be apparent to those of ordinary skill in the art in viewof the teachings herein.

FIG. 32 shows an exemplary therapeutic agent delivery system (800) thatincludes a harmonic surgical instrument (802) having a handpiece (804),a shaft (806), and an end effector (810). End effector (810) includes aharmonic blade (812) and a pivotable clamp pad (814). Harmonic blade(812) is energized by an ultrasonic transducer (813), which receivespower from a cable (818) that is coupled with a generator (not shown).End effector (810) is operable to administer a therapeutic agent (820).It should therefore be understood that harmonic surgical instrument(802) may be configured and operable in accordance with any of the aboveteachings in sections V.B.2, V.D.1, and/or V.D.2. Of course, harmonicsurgical instrument (802) may have any other suitable configurationand/or operability; and may even be a different kind of medical device.In the present example, handpiece (804) includes a fluid coupling (822),which is in fluid communication with end effector (810). A conduit (824)is coupled with coupling (822), such that conduit (824) is in fluidcommunication with end effector (810) via coupling (822). A bag (826) isalso coupled with conduit (824). Bag (826) of this example includes aconventional IV bag containing therapeutic agent (820), though it shouldbe understood that bag (826) may have any other suitable construction.Therapeutic agent (820) may comprise any therapeutic agent referred toherein or any other suitable type of therapeutic agent that will beapparent to those of ordinary skill in the art in view of the teachingsherein. In some versions, bag (826) is positioned vertically higher thanharmonic surgical instrument (802) during use of harmonic surgicalinstrument (802), such that therapeutic agent (820) is at leastpartially fed to end effector (810) by gravity. Of course, system (800)may also include one or more pumps that are operable to drivetherapeutic agent (820) to end effector (810), including but not limitedto any of the various kinds of pumps described below.

FIG. 33 shows an exemplary harmonic surgical instrument (830) having ahandpiece (832) with integral therapeutic agent cartridges (834).Cartridges (834) are in fluid communication with a conduit (836), whichextends distally through shaft (838) alongside waveguide (840). Conduit(836) and waveguide (840) extend to an end effector (not shown) that ispositioned at the distal end of shaft (838). The end effector isoperable to administer a therapeutic agent (842) from cartridges (834).It should therefore be understood that harmonic surgical instrument(830) may be configured and operable in accordance with any of the aboveteachings in sections V.B.2, V.D.1, and/or V.D.2. Of course, harmonicsurgical instrument (830) may have any other suitable configurationand/or operability; and may even be a different kind of medical device.It should be understood that cartridges (834) may be modular, eachcontaining its own kind of therapeutic agent (842), such that a user mayselect from various cartridges (834) to tailor treatment to a givenpatient based on any suitable factors such as biomarker data, the kindof procedure in which harmonic surgical instrument (830) is being used,the location in the patient's anatomy in which harmonic surgicalinstrument (830) is being used, etc. By accommodating several cartridges(834), harmonic surgical instrument (830) further allows two or moretherapeutic agents (842) to be combined for administration as a cocktailat the end effector. While handpiece (832) is shown with threecartridges (834), it should be understood that handpiece (832) may bemade to accommodate any other suitable number of cartridges (834), suchas one, two, or more than three.

In some versions, all cartridges provide therapeutic agent (842) toconduit (836) substantially simultaneously. In some other versions,handpiece (832) includes one or more valves (not shown) that allowtherapeutic agent (842) to be selectively communicated from one or morecartridges (834) at any given time. For instance, one kind oftherapeutic agent (842) may be communicated from only one of thecartridges (834) before a surgical procedure begins; with a second kindof therapeutic agent (842) being communicated from one of the othercartridges (834) during the surgical procedure; and with a third kind oftherapeutic agent (842) being communicated from another one of the othercartridges (834) at the end of the surgical procedures. Various suitableways in which handpiece (832) may be configured to provide suchselective use of catridges (834) will be apparent to those of ordinaryskill in the art in view of the teachings herein.

In the present example, the location and orientation of cartridges (834)in handpiece (832) allows therapeutic agent (842) to be at leastpartially fed to the end effector by gravity. Of course, harmonicsurgical instrument (830) may also include one or more pumps that areoperable to drive therapeutic agent (842) to the end effector, includingbut not limited to any of the various kinds of pumps described below. Itshould also be understood that harmonic surgical instrument (830) may beat least partially configured in accordance with the teachings of U.S.Pat. No. 7,673,783, entitled “Surgical Stapling Instruments Structuredfor Delivery of Medical Agents,” issued Mar. 9, 2010, the disclosure ofwhich is incorporated by reference herein. While U.S. Pat. No. 7,673,783is provided in the context of a surgical stapling instrument, those ofordinary skill in the art will recognize that several of the teachingsof U.S. Pat. No. 7,673,783 may be readily applied to harmonic surgicalinstrument (830). It should also be understood that a surgical stapler(or other medical device) constructed in accordance with the teachingsof U.S. Pat. No. 7,673,783 may be used to administer a therapeutic agentbased on biomarker data or otherwsise, in accordance with the teachingsherein.

FIGS. 34 and 35A-B show another exemplary harmonic surgical instrument(860), which is a merely illustrative variation of harmonic surgicalinstrument (830) shown in FIG. 33. In this example, harmonic surgicalinstrument (860) includes a handpiece (862) with integral therapeuticagent cartridges (864). Cartridges (864) are in fluid communication witha conduit (866), which extends distally through shaft (868) alongside awaveguide (not shown). Conduit (866) and the waveguide extend to an endeffector (not shown) that is positioned at the distal end of shaft(868). The end effector is operable to administer a therapeutic agent(872) from cartridges (864). It should therefore be understood thatharmonic surgical instrument (860) may be configured and operable inaccordance with any of the above teachings in sections V.B.2, V.D.1,and/or V.D.2. Of course, harmonic surgical instrument (860) may have anyother suitable configuration and/or operability; and may even be adifferent kind of medical device. It should be understood thatcartridges (864) may be modular, as described above with respect toharmonic surgical instrument (830). While handpiece (862) is shown withthree cartridges (864), it should be understood that handpiece (862) maybe made to accommodate any other suitable number of cartridges (864),such as one, two, or more than three.

In some versions, all cartridges provide therapeutic agent (872) toconduit (866) substantially simultaneously. In some other versions,handpiece (862) includes one or more valves (not shown) that allowtherapeutic agent (872) to be selectively communicated from one or morecartridges (864) at any given time, as described above with respect toharmonic surgical instrument (830). Similarly, the location andorientation of cartridges (864) in handpiece (862) allows therapeuticagent (872) to be at least partially fed to the end effector by gravity.Of course, harmonic surgical instrument (860) may also include one ormore pumps that are operable to drive therapeutic agent (872) to the endeffector, including but not limited to any of the various kinds of pumpsdescribed below. It should also be understood that harmonic surgicalinstrument (860) may be at least partially configured in accordance withthe teachings of U.S. Pat. No. 7,673,783, entitled “Surgical StaplingInstruments Structured for Delivery of Medical Agents,” issued Mar. 9,2010, the disclosure of which is incorporated by reference herein.

Handpiece (862) of the present example also includes a pair of buttons(880, 882). Buttons (880, 882) are operable to selectively activate aharmonic blade at the end effector. For instance, one button (880) mayprovide maximum intensity while the other button (882) provides minimumintensity. Harmonic surgical instrument (860) of this example isconfigured such that either button (880, 882) must be held down in orderto keep the harmonic blade in an active state, such that the harmonicblade returns to an inactive state as soon as a held button (880, 882)is released. Buttons (880, 882) are thus operable similar to buttons(142, 144) of device (100) described above.

Conduit (866) of the present example includes a variable restrictionregion (890) within handpiece (862). A variable restriction member (892)is positioned for selective contact with conduit (866) in this region(890), as best seen in FIGS. 35A-B. Variable restriction member (892)includes a conduit contact ball (894) and a lever arm (896); and ispivotable about a pin (898) that is fixedly secured in handpiece (862).Variable restriction member (892) is positioned in handpiece (862) suchthat buttons (880, 882) contact lever arm (896). Variable restrictionmember (892) is also resiliently biased (e.g., by a spring, etc.) tomaintain a substantially vertical orientation as shown in FIG. 35A whenneither button (880, 882) is being depressed. In this position, contactball (894) pinches conduit (866) at region (890), effectively closingoff conduit (866) at region (890). It should be understood that acontact surface (not shown) may be positioned above conduit (866) atregion (890) to substantially prevent deformation of the top portion ofconduit (866) at region (890), allowing contact ball (894) toeffectively pinch conduit (866) closed at region (890) when variablerestriction member (892) is in the upright position. Thus, in thisexample, no therapeutic agent (872) is communicated through conduit(866) past region (890) when neither button (880, 882) is beingdepressed. In other words, therapeutic agent (872) is only administeredat the end effector when the harmonic blade is being activated by abutton (880, 882) in this example.

As shown in FIG. 35B, therapeutic agent (872) is able to travel throughconduit (866) past region (890) when either button (880, 882) isdepressed, though the flow rate permitted through region (890) is basedon which button (880, 882) is being depressed. In particular, whenbutton (882) is depressed as indicated by arrow (886) to activate theharmonic blade at the minimum intensity, variable restriction member(892) is pivoted to a first rotational position. In this first position,contact ball (894) partially relieves conduit (866) of pinching yetstill pinches conduit (866) enough to provide a reduced flow oftherapeutic agent (872) through conduit (866). When button (880) isdepressed as indicated by arrow (884) to activate the harmonic blade atmaximum intensity, variable restriction member (892) is pivoted to asecond rotational position. In this second position, contact ball (894)fully relieves conduit (866) of pinching to provide full flow oftherapeutic agent (872) through conduit (866). Thus, in this example,the flow rate of therapeutic agent (872) to the end effector is tieddirectly to the intensity at which the harmonic blade oscillates.Various other suitable ways in which the flow rate of a therapeuticagent (872) may be tied to the intensity at which a harmonic bladeoscillates (and/or be tied to some other operating parameter of amedical device) will be apparent to those of ordinary skill in the artin view of the teachings herein.

FIG. 36 shows yet another exemplary harmonic surgical instrument (900),which is another merely illustrative variation of harmonic surgicalinstrument (830) shown in FIG. 33. In this example, harmonic surgicalinstrument (900) includes a handpiece (902) with integral therapeuticagent cartridges (904). Cartridges (904) are in fluid communication witha conduit (906), which extends distally through shaft (908) alongside awaveguide (not shown). Conduit (906) and the waveguide extend to an endeffector (not shown) that is positioned at the distal end of shaft(908). The end effector is operable to administer a therapeutic agent(912) from cartridges (904). It should therefore be understood thatharmonic surgical instrument (900) may be configured and operable inaccordance with any of the above teachings in sections V.B.2, V.D.1,and/or V.D.2. Of course, harmonic surgical instrument (900) may have anyother suitable configuration and/or operability; and may even be adifferent kind of medical device. It should be understood thatcartridges (904) may be modular, as described above with respect toharmonic surgical instrument (830). While handpiece (902) is shown withthree cartridges (904), it should be understood that handpiece (902) maybe made to accommodate any other suitable number of cartridges (904),such as one, two, or more than three.

In some versions, all cartridges provide therapeutic agent (912) toconduit (906) substantially simultaneously. In some other versions,handpiece (902) includes one or more valves (not shown) that allowtherapeutic agent (912) to be selectively communicated from one or morecartridges (904) at any given time, as described above with respect toharmonic surgical instrument (830). Similarly, the location andorientation of cartridges (904) in handpiece (902) allows therapeuticagent (912) to be at least partially fed to the end effector by gravity.Of course, harmonic surgical instrument (900) may also include one ormore pumps that are operable to drive therapeutic agent (912) to the endeffector, including but not limited to any of the various kinds of pumpsdescribed below. It should also be understood that harmonic surgicalinstrument (900) may be at least partially configured in accordance withthe teachings of U.S. Pat. No. 7,673,783, entitled “Surgical StaplingInstruments Structured for Delivery of Medical Agents,” issued Mar. 9,2010, the disclosure of which is incorporated by reference herein.

Handpiece (902) of the present example includes a pistol grip (920), atrigger member (922), and a primer pump (924). Trigger member (922) ispivotable relative to pistol grip (920) to pivot a clamp pad (not shown)at the end effector toward a harmonic blade (not shown) at the endeffector. Trigger member (922) is thus operable similar to triggermember (150) of device (100) described above. Primer pump (924) iscoupled with a pump conduit (926), which is further coupled with aY-fitting (928). Y-fitting (928) is in fluid communication withcartridges (904) and conduit (906). Primer pump (924) is operable todrive therapeutic agent (912) distally through conduit (906) when primerpump (924) is squeezed. To that end, trigger member (922) includes aprotrusion (930) positioned adjacent to primer pump (924). Protrusion(930) is positioned and configured such that protrusion (930) squeezesprimer pump (924) when trigger member (922) is pivotally squeezed towardpistol grip (920). Thus, harmonic surgical instrument (900) dispensestherapeutic agent (912) at the end effector when the clamp pad ispivoted toward the harmonic blade at the end effector by trigger member(922). Various other suitable ways in which the dispensation of atherapeutic agent (912) may be tied to the actuation of a clamp pad in aharmonic surgical instrument (and/or be tied to some other operatingparameter of a medical device) will be apparent to those of ordinaryskill in the art in view of the teachings herein.

FIG. 37 shows yet another exemplary harmonic surgical instrument (940),which is yet another merely illustrative variation of harmonic surgicalinstrument (830) shown in FIG. 33. In this example, harmonic surgicalinstrument (940) includes a handpiece (942) with integral therapeuticagent cartridges (944). Cartridges (944) are in fluid communication witha conduit (946), which extends distally through shaft (948) alongside awaveguide (not shown). Conduit (946) and the waveguide extend to an endeffector (not shown) that is positioned at the distal end of shaft(948). The end effector is operable to administer a therapeutic agent(952) from cartridges (404). It should therefore be understood thatharmonic surgical instrument (940) may be configured and operable inaccordance with any of the above teachings in sections V.B.2, V.D.1,and/or V.D.2. Of course, harmonic surgical instrument (940) may have anyother suitable configuration and/or operability; and may even be adifferent kind of medical device. It should be understood thatcartridges (944) may be modular, as described above with respect toharmonic surgical instrument (830). While handpiece (942) is shown withthree cartridges (904), it should be understood that handpiece (942) maybe made to accommodate any other suitable number of cartridges (944),such as one, two, or more than three.

In some versions, all cartridges provide therapeutic agent (952) toconduit (946) substantially simultaneously. In some other versions,handpiece (942) includes one or more valves (not shown) that allowtherapeutic agent (952) to be selectively communicated from one or morecartridges (944) at any given time, as described above with respect toharmonic surgical instrument (830). Similarly, the location andorientation of cartridges (944) in handpiece (942) allows therapeuticagent (952) to be at least partially fed to the end effector by gravity.Of course, harmonic surgical instrument (940) may also include one ormore pumps that are operable to drive therapeutic agent (952) to the endeffector, including but not limited to any of the various kinds of pumpsdescribed below. It should also be understood that harmonic surgicalinstrument (940) may be at least partially configured in accordance withthe teachings of U.S. Pat. No. 7,673,783, entitled “Surgical StaplingInstruments Structured for Delivery of Medical Agents,” issued Mar. 9,2010, the disclosure of which is incorporated by reference herein.

Handpiece (942) of the present example includes a valve box (960) and anelectromechanical pump (962), both of which are interposed betweencartridges (944) and conduit (946). Handpiece (942) also includes a pairof buttons (964, 966). Buttons (964, 966) are operable to selectivelyactivate a harmonic blade at the end effector. For instance, one button(964) may provide maximum intensity while the other button (966)provides minimum intensity. Harmonic surgical instrument (940) of thisexample is configured such that either button (964, 966) must be helddown in order to keep the harmonic blade in an active state, such thatthe harmonic blade returns to an inactive state as soon as a held button(964, 966) is released. Buttons (964, 966) are thus operable similar tobuttons (142, 144) of device (100) described above. In the presentexample, control of valve box (960) and pump (962) is tied to activationof buttons (964, 966). In particular, handpiece (942) is configured suchthat valve box (960) only opens one or more valves between cartridges(944) and pump (962) only when a button (964, 966) is depressed. Whenneither button (964, 966) is being depressed, valve box (960) closes offfluid communication from cartridges (944) to pump (962) in this example.

In addition, handpiece (942) of the present example is configured suchthat pump (962) drives therapeutic agent (952) distally through conduit(946) only when a button (964, 966) is depressed. When neither button(964, 966) is being depressed, pump (962) is simply deactivated. Thus,in this example, no therapeutic agent (952) is communicated to the endeffector when neither button (964, 966) is depressed. In other words,therapeutic agent (952) is only administered at the end effector whenthe harmonic blade is being activated by a button (964, 966) in thisexample. Of course, harmonic surgical instrument (940) may alternativelybe configured such that valve box (960) and/or pump (962) are operableindependently relative to buttons (964, 966), such that therapeuticagent (952) may be administered at times when the harmonic blade is notbeing activated. It should also be understood that harmonic surgicalinstrument (940) may be configured such that the flow rate throughconduit (946) is based on which button (964, 966) is being depressed.Furthermore, it should be understood that pump (962) may be configuredsuch that therapeutic agent (952) is not communicable through pump (962)when pump (962) is deactivated, such that valve box (960) may simply beomitted in some versions. In the present example, pump (962) receivespower from the same cable (968) that drives ultrasonic transducer (969)(which in turn drives the harmonic blade at the end effector), though itshould be understood that pump (962) may be powered in any othersuitable fashion (e.g., by a battery positioned in handpiece (942).Various other suitable components, features, configurations, andoperabilities that may be provided in harmonic surgical instrument (940)will be apparent to those of ordinary skill in the art in view of theteachings herein.

FIGS. 38-39 show merely illustrative examples of pumping components thatmay be included in pump (962) of harmonic surgical instrument (940). Inparticular, FIG. 38 shows a pump (970) that includes a pump housing(972) with an inlet (974) and an outlet (976). Referring back toharmonic surgical instrument (940) of FIG. 37, inlet (974) may becoupled with valve box (960) (or directly with cartridges (944) inversions where valve box (960) is omitted); while outlet (976) iscoupled with conduit (946). A pump wheel (978) is provided withinhousing (972) and is rotatable about an axle (980). Pump wheel (978)includes a plurality of outwardly extending fins (982) providing a starshaped cross sectional profile. While four fins (982) are shown itshould be understood that any suitable number of fins (982) may be used.Fins (982) are configured to drive therapeutic agent (952) from inlet(974) toward outlet (976) when pump wheel (978) is rotated about axle(980). In some versions, this rotation of pump wheel (978) drivestherapeutic agent (952) through outlet (976) and conduit (946) in apulsed stream. In some other versions, this rotation of pump wheel (978)drives therapeutic agent (952) through outlet (976) and conduit (946) ina continuous stream.

FIG. 39 shows a pump (985) that includes a pump housing (986) with aninlet (988) and an outlet (990). Referring again back to harmonicsurgical instrument (940) of FIG. 37, inlet (988) may be coupled withvalve box (960) (or directly with cartridges (944) in versions wherevalve box (960) is omitted); while outlet (990) is coupled with conduit(946). A pump wheel (992) is provided within housing (986) and isrotatable within housing (986). A pair of driving cylinders (994) aresecured to the exterior of pump wheel (992) and rotate unitarily withpump wheel (992). While two driving cylinders (994) are shown it shouldbe understood that any suitable number of driving cylinders (994) may beused. Driving cylinders (994) are configured to drive therapeutic agent(952) from inlet (988) toward outlet (990) when pump wheel (992) isrotated within housing (986). In some versions, this rotation of pumpwheel (991) drives therapeutic agent (952) through outlet (990) andconduit (946) in a pulsed stream. In some other versions, this rotationof pump wheel (992) drives therapeutic agent (952) through outlet (990)and conduit (946) in a continuous stream. Various other suitable ways inwhich pump (962) may be configured will be apparent to those of ordinaryskill in the art in view of the teachings herein.

4. Exemplary Administration of Therapeutic Agent Separate from SurgicalDevice

The examples described below relate to various additional structures andmethods that may be used to provide communication of a therapeutic agentto a surgical site or other wound site. By way of example only, thebelow teachings may be readily incorporated with any of the teachingsprovided in section V.B.2, above. Still other settings in which thebelow teachings may be readily applied will be apparent to those ofordinary skill in the art in view of the teachings herein. It shouldalso be understood that various components, features, and operabilitiesof the below examples may be readily combined with each other in variousways, as will be apparent to those of ordinary skill in the art in viewof the teachings herein.

FIG. 40 shows a pair of trocars (1002) inserted through the abdominalwall (1000) of a patient. A therapeutic agent delivery device (1004) isdisposed through one of the trocars (1002) while the shaft (1006) of aharmonic surgical device is disposed through the other trocar (1002). Aplunger (1010) of the therapeutic agent delivery device (1004) isdepressed to administer a therapeutic agent (1008) at a surgical site,adjacent to the end effector (1012) at the distal end of shaft (1006).In some versions, this is done to pre-soak the patient's tissue withtherapeutic agent (1008) at the surgical site before the harmonic blade(1014) of end effector (1012) is activated. In addition or in thealternative, therapeutic agent (1008) may be administered at thesurgical site during activation of harmonic blade (1014) and/or afterharmonic blade (1014) has been activated then de-activated. In someinstances, different therapeutic agent delivery devices (1004)containing different therapeutic agents (1008) may be fed through trocar(1002) at different stages during surgery. Thus, while several aboveexamples relate to surgical instruments that create wounds duringsurgery also being used to administer a therapeutic agent, it should beunderstood that a completely separate device may be used to administer atherapeutic agent. It should also be understood that, as with all otherexamples described herein, therapeutic agent (1008) may be selected andadministered based on biomarker data and/or based on various otherfactorsr.

FIG. 41 shows another exemplary therapeutic agent delivery device(1020). Therapeutic agent delivery device (1020) of this exampleincludes a handpiece (1030) and a shaft (1040) extending distally fromhandpiece (1030). Handpiece (1030) of this example includes anirrigation button (1032) and a suction button (1036). Shaft (1040) ofthis example is substantially hollow, and the distal end of shaft (1040)includes a distal opening (1042) and a plurality of side openings(1044), such that shaft (1040) is operable to dispense various fluidsfrom handpiece (1030) as described below. An irrigation tube (1034) anda suction tube (1038) are coupled with handpiece (1030). In someversions, irrigation tube (1034) is further coupled with a source ofsaline. In some other versions, irrigation tube (1034) coupled with asource of therapeutic agent (1052). In addition, suction tube (1038) iscoupled with a conventional suction source in some versions. In someother versions, suction tube (1038) is coupled with a capture vessel(180) or a biomarker processing module (230) as described above.Irrigation button (1032) is operable to selectively couple shaft (1040)with irrigation tube (1034); while suction button (1036) is operable toselectively couple shaft (1040) with suction tube (1038).

Handpiece (1030) also includes a therapeutic agent cartridge (1050) andis operable to selectively couple shaft (1040) with cartridge (1050).For instance, in some versions, shaft (1040) is coupled with cartridge(1050) when irrigation button (1032) is activated, such that saline orsome other fluid medium communicated through irrigation tube (1034)drives therapeutic agent (1052) from cartridge (1050) through openings(1042, 1044) at the distal end of shaft (1040) when irrigation button(1032) is activated. Alternatively, a separate button or other featuremay be provided to selectively administer therapeutic agent (1052) fromcartridge (1050) through openings (1042, 1044).

In some versions, shaft (1040) is sized to fit through a trocar. Thus,referring back to FIG. 40, and by way of example only, shaft (1040) maybe fed through a trocar (1002) instead of feeding therapeutic agentdelivery device (1004) through trocar (1002). With the distal end ofshaft (1040) positioned adjacent to a surgical site or other wound site,suction button (1036) may be activated (e.g., while harmonic blade(1014) is activated) to obtain biomarker data in accordance with block(10) of FIG. 1, in accordance with the teachings of section V.A., above,and/or in accordance with other teachings herein. Irrigation button(1032) (or some other feature) may then be used to administertherapeutic agent (1052) at the surgical site or other wound site basedon the acquired biomarker data, in accordance with block (60) of FIG. 1,in accordance with the teachings of section V.B., above, and/or inaccordance with other teachings herein. In addition or in thealternative, other actions may be taken in response to the biomarkerdata (e.g., in accordance with blocks (70, 80, and/or 90) of FIG. 1).Still other suitable ways in which therapeutic agent delivery device(1020) may be configured and used will be apparent to those of ordinaryskill in the art in view of the teachings herein.

FIGS. 42-43 show another exemplary structure and method for delivering atherapeutic agent to a surgical site or other wound site. In particular,FIG. 42 shows a therapeutic agent pad (1060) impregnated with atherapeutic agent (1062). In this example, therapeutic agent (1062)comprises a gene therapy substance, but as with all other examplesdescribed herein, therapeutic agent (1062) may alternatively compriseany other suitable therapeutic agent. In an exemplary use, pad (1060) isplaced against a patient's tissue (1070). Then, a harmonic blade (1080)of a harmonic surgical instrument is positioned over pad (1060), suchthat pad (1060) is interposed between harmonic blade (1080) and thepatient's tissue (1070). When harmonic blade (1080) is activated,harmonic blade (1080) provides sonoporation in the patient's tissue(1070) as described above, while simultaneously driving therapeuticagent (1062) from pad (1060) into the patient's tissue (1070). Varioussuitable structures and materials that may be used for pad (1060) willbe apparent to those of ordinary skill in the art in view of theteachings herein.

Versions of the devices described above may have application inconventional medical treatments and procedures conducted by a medicalprofessional, as well as application in robotic-assisted medicaltreatments and procedures.

Versions of described above may be designed to be disposed of after asingle use, or they can be designed to be used multiple times. Versionsmay, in either or both cases, be reconditioned for reuse after at leastone use. Reconditioning may include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, someversions of the device may be disassembled, and any number of theparticular pieces or parts of the device may be selectively replaced orremoved in any combination. Upon cleaning and/or replacement ofparticular parts, some versions of the device may be reassembled forsubsequent use either at a reconditioning facility, or by a userimmediately prior to a procedure. Those skilled in the art willappreciate that reconditioning of a device may utilize a variety oftechniques for disassembly, cleaning/replacement, and reassembly. Use ofsuch techniques, and the resulting reconditioned device, are all withinthe scope of the present application.

By way of example only, versions described herein may be sterilizedbefore and/or after a procedure. In one sterilization technique, thedevice is placed in a closed and sealed container, such as a plastic orTYVEK bag. The container and device may then be placed in a field ofradiation that can penetrate the container, such as gamma radiation,x-rays, or high-energy electrons. The radiation may kill bacteria on thedevice and in the container. The sterilized device may then be stored inthe sterile container for later use. A device may also be sterilizedusing any other technique known in the art, including but not limited tobeta or gamma radiation, ethylene oxide, or steam.

Having shown and described various versions in the present disclosure,further adaptations of the methods and systems described herein may beaccomplished by appropriate modifications by one of ordinary skill inthe art without departing from the scope of the present invention.Several of such potential modifications have been mentioned, and otherswill be apparent to those skilled in the art. For instance, theexamples, versions, geometries, materials, dimensions, ratios, steps,and the like discussed above are illustrative and are not required.Accordingly, the scope of the present invention should be considered interms of the following claims and is understood not to be limited to thedetails of structure and operation shown and described in thespecification and drawings.

I/We claim:
 1. An apparatus, comprising: (a) a handpiece; (b) a shaftextending distally from the handpiece, wherein the shaft includes adistal end; (c) a conduit extending through the shaft; (d) an endeffector positioned at the distal end of the shaft, wherein the endeffector includes a port in fluid communication with the conduit; and(e) a biomarker collection assembly in fluid communication with theconduit, wherein the biomarker collection assembly is configured to drawin biomarkers through the port and store or process the biomarkers. 2.The apparatus of claim 1, wherein the biomarker collection assemblycomprises a suction pump, wherein the suction pump is integral with thehandpiece.
 3. The apparatus of claim 1, wherein the biomarker collectionassembly comprises a suction pump, wherein the end effector furthercomprises an active element operable to create a wound in tissue whenthe active element is activated, wherein the suction pump is configuredto create suction in the conduit in response to activation of the activeelement.
 4. The apparatus of claim 3, wherein the active elementcomprises a harmonic blade.
 5. The apparatus of claim 1, wherein thebiomarker collection assembly comprises a capture vessel removablycoupled with the handpiece, wherein the capture vessel is configured tostore biomarkers drawn in through the conduit.
 6. The apparatus of claim1, wherein the biomarker collection assembly comprises a biomarkersensor configured to detect biomarkers communicated through the conduit.7. The apparatus of claim 6, wherein the biomarker sensor comprises acantilever beam coupled with a shaft, wherein the cantilever beamcomprises one or more substances selected to attract one or morespecific biomarkers, such that the one or more specific biomarkers willcollect on the beam as a fluid containing the biomarkers is communicatedacross the beam.
 8. The apparatus of claim 7, wherein the biomarkercollection assembly further comprises a sensor reader configured todetect one or both of movement within the sensor or an increase in themass of the beam.
 9. The apparatus of claim 7, wherein the one or moresubstances comprise one or more of an antibody or an amino acid.
 10. Theapparatus of claim 1, wherein the biomarker collection assembly furtherincludes one or both of a communication port or a graphical userinterface configured to communicate biomarker data.
 11. An apparatus,comprising: (a) a handpiece; (b) a shaft extending distally from thehandpiece, wherein the shaft includes a distal end; (c) a conduitextending through the shaft; (d) an end effector positioned at thedistal end of the shaft, wherein the end effector comprises a harmonicblade, wherein the end effector is in fluid communication with theconduit; and (e) a therapeutic agent administration assembly in fluidcommunication with the conduit, wherein the therapeutic agentadministration assembly is operable to administer a therapeutic agentthrough the end effector.
 12. The apparatus of claim 11, wherein theharmonic blade includes at least one opening in fluid communication withthe conduit.
 13. The apparatus of claim 11, wherein the harmonic bladeincludes at least one recess in fluid communication with the conduit.14. The apparatus of claim 11, further comprising a sheath disposedabout a portion of the harmonic blade, wherein the sheath and theharmonic blade together selectively open a gap in fluid communicationwith the conduit when the harmonic blade is in an activated state,wherein the gap is closed when the harmonic blade is in a non-activatedstate.
 15. The apparatus of claim 11, wherein the end effector furthercomprises a clamp pad, wherein the clamp pad is pivotable relative tothe harmonic blade.
 16. The apparatus of claim 15, wherein the clamp padcomprises one or more openings in fluid communication with the conduit.17. The apparatus of claim 16, wherein the one or more openingscomprises one or more variable orifices, wherein each orifice isconfigured transition between a closed state and an open state inresponse to a control signal.
 18. The apparatus of claim 16, whereineach opening is associated with a respective cell, wherein each celldefines a reservoir containing the therapeutic agent, wherein each cellis configured to drive the therapeutic agent from the cell and outthrough the corresponding opening in response to a control signal. 19.An apparatus, comprising: (a) a handpiece; (b) a shaft extendingdistally from the handpiece, wherein the shaft includes a distal end;(c) an end effector positioned at the distal end of the shaft; (d) abiomarker collection assembly in fluid communication with the endeffector, wherein the biomarker collection assembly is configured todraw in biomarkers through the end effector and store or process thebiomarkers; and (e) a biomarker response assembly, wherein the biomarkerresponse assembly is operable to either: (i) change an operatingparameter of the end effector based at least in part on biomarker datafrom the biomarker assembly, or (ii) administer a therapeutic agentthrough the end effector based at least in part on biomarker data fromthe biomarker collection assembly.
 20. The apparatus of claim 19,further comprising a conduit extending through the shaft, wherein theconduit is in fluid communication with one or both of the biomarkercollection assembly or the biomarker response assembly, wherein the endeffector further comprises: (i) an active element operable to create awound in tissue when the active element is activated, and (ii) a port influid communication with the conduit, wherein the port is positionedadjacent to the active element.